Small molecule mdm2 protein degraders

ABSTRACT

The present disclosure provides compounds represented by Formula I:wherein R1a, R1b, R2a, R2b, R3a, R3b, R4, A, L, X, Y, and Z are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat cancer or any other disease, condition, or disorder that is responsive to degradation of MDM2 protein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of Ser. No. 16/594,344 filed Oct. 7,2019, which claims the benefit of U.S. Provisional Patent applicationNo. 62/742,627, filed Oct. 8, 2018, incorporated herein by reference inits entirety.

STATEMENT OF GOVERNMENT INTEREST

This invention was made with government support under CA219345 awardedby the National Institutes of Health. The government has certain rightsin the invention.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure provides MDM2 protein degraders and therapeuticmethods of treating conditions and diseases wherein degradation of MDM2provides a benefit

Background

The p53 tumor suppressor is a principal mediator of growth arrest,senescence, and apoptosis in response to a broad array of cellulardamage. Rapid induction of high p53 protein levels by various stresstypes prevents inappropriate propagation of cells carrying potentiallymutagenic, damaged DNA. p53 can kill cells via a dualtranscription-dependent and -independent function in the nucleus and atthe mitochondria. It has been demonstrated that cellular p53 proteinlevels are the single most important determinant of its function. Innormal unstressed cells, p53 is a very unstable protein with a half-liferanging from 5 to 30 min, which is present at very low cellular levelsowing to continuous degradation largely mediated by MDM2. Conversely, ahallmark of many cellular stress pathways such as DNA damage, hypoxia,telomere shortening, and oncogene activation is the rapid stabilizationof p53 via a block of its degradation. MDM2 has emerged as the principalcellular antagonist of p53 by limiting the p53 tumor suppressorfunction. Moll and Petrenko, Molecular Cancer Research 1:1001-1008(2003).

MDM2 is transcriptionally activated by p53 and MDM2, in turn, inhibitsp53 activity by at least three mechanisms. Wu et al., Genes Dev. 7:1126(1993). First, MDM2 protein directly binds to the p53 transactivationdomain and thereby inhibits p53-mediated transactivation. Second, MDM2protein contains a nuclear export signal sequence, and upon binding top53, induces the nuclear export of p53, preventing p53 from binding tothe targeted DNAs. Third, MDM2 protein is an E3 ubiquitin ligase andupon binding to p53 is able to promote p53 degradation.

Small-molecule inhibitors that target the p53-MDM2 interaction havetherapeutic potential for treating cancer and other diseases. Chene,Nat. Rev. Cancer 3:102 (2003) and Vassilev et al., Science 303:844(2004). Antagonists of the p53-MDM2 interaction are described in U.S.Pat. Nos. 7,759,383; 7,737,174; 8,518,984; 8,680,132; 8,629,141;6,617,346; 6,734,302; 7,132,421; 7,425,638; 7,579,368; 7,060,713;7,553,833; 6,916,833; 7,495,007; 7,638,548; 7,576,082; 7,625,895; and7,083,983; and U.S. Patent Application Publication Nos. 2005/0288287;2009/0143364; 2009/0312310; 2006/0211718; 2010/0048593; 2005/0227932;2008/0261917; 2009/0227542; 2008/0171723; 2006/0211757; 2005/0137137;2002/0132977; and 2009/0030181.

Phthalimide-based drugs, e.g., thalidomide or lenalidomide, bind toprotein-degradation machinery, e.g., cereblon (CRBN; part of anubiquitin E3 ligase complex). This may promote the recruitment of twotranscription factors (IKZF1 and IKZF3) that are essential to diseaseprogression, resulting in drug-induced ubiquitylation and degradation bythe proteasome. See, e.g., Ito et al., Science 327:1345-1350 (2010) andWinter et al., Science 348:1376-1381 (2015).

A high-affinity VHL ligand, see Bondeson et al., Nat. Chem. Biol.11:611-617 (2015), may recruit a target protein to an E3 ubiquitinligase, resulting in drug induced ubiquitination and degradation. See,e.g., van Hagen et al., Nucleic Acids Research 38: 1922-1931 (2010);Buckley et al., J. Am. Chem. Soc. 134:4465-4468 (2012); Buckley et al.,Angew, Chem. Int. Ed. Engl. 51:11463-11467 (2012); Lipkowitz andWeissman, Nat Rev Cancer 11:629-643 (2011); and Zengerle et al., ACSChem. Biol. 10:1770-1777 (2015).

There is an ongoing need for new agents, e.g., small molecules, fortreating cancer and other diseases responsive to the disruption orprevention of the MDM2-p53 interaction.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides heterobifunctionalcompounds represented by Formula I or Formula II, below, and thepharmaceutically acceptable salts and solvates thereof, collectivelyreferred to as “Compounds of the Disclosure.” Compounds of theDisclosure are MDM2 protein degraders and thus are useful in treatingdiseases or conditions wherein inhibition and/or degradation of MDM2provides a benefit.

In another aspect, the present disclosure provides methods of treating acondition or disease by administering a therapeutically effective amountof a Compound of the Disclosure to a subject, e.g., a human, in needthereof. The disease or condition of interest is treatable bydegradation of MDM2 proteins, for example, a cancer, a chronicautoimmune disorder, an inflammatory condition, a proliferativedisorder, sepsis, or a viral infection. Also provided are methods ofpreventing the proliferation of unwanted proliferating cells, such as incancer, in a subject comprising administering a therapeuticallyeffective amount of a Compound of the Disclosure to a subject at risk ofdeveloping a condition characterized by unwanted proliferating cells. Insome embodiments, the Compounds of the Disclosure reduce theproliferation of unwanted cells by inducing apoptosis in those cells.

In another aspect, the present disclosure provides a method of degradingMDM2 proteins in a subject, comprising administering to the subject aneffective amount of at least one Compound of the Disclosure.

In another embodiment, the present disclosure provides a method ofreducing MDM2 protein within a cell of a subject, e.g., a human patientin need thereof, the method comprising administering a Compound of theDisclosure to the subject.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Disclosure and an excipientand/or pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a compositioncomprising a Compound of the Disclosure and an excipient and/orpharmaceutically acceptable carrier for use treating diseases orconditions wherein degradation of MDM2 proteins provides a benefit,e.g., cancer.

In another aspect, the present disclosure provides a compositioncomprising: (a) a Compound of the Disclosure; (b) a secondtherapeutically active agent; and (c) optionally an excipient and/orpharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a Compound of theDisclosure for use in treatment of a disease or condition of interest,e.g., cancer.

In another aspect, the present disclosure provides a use of a Compoundof the Disclosure for the manufacture of a medicament for treating adisease or condition of interest, e.g., cancer.

In another aspect, the present disclosure provides a kit comprising aCompound of the Disclosure, and, optionally, a packaged compositioncomprising a second therapeutic agent useful in the treatment of adisease or condition of interest, and a package insert containingdirections for use in the treatment of a disease or condition, e.g.,cancer.

In another aspect, the present disclosure provides a method of treatinga subject having a hematological cancer, the method comprising:

(a) determining whether an overexpression of MDM2 is present or absentin a biological sample taken from the subject; and

(b) administering a therapeutically effective amount of a compound of aCompound of the Disclosure to the subject if an overexpression of MDM2is present in the biological sample.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF DRAWINGS

FIG. 1 is a line graph showing in vivo antitumor activity of Cpd. No. 4and Cpd. No. 6 in the LNCaP prostate cancer xenograft model in SCIDmice. Drug was administered I.V., once per week at 50 mg/kg for 5 weeks.Each group had seven mice with each mouse bearing one tumor.

FIG. 2 is a line graph showing in vivo antitumor activity of Cpd. No. 4and Cpd. No. 6 in the 22rv1 prostate cancer xenograft model in SCIDmice. Drug was administered I.V., once per week at 50 mg/kg for 3 weeks.Each group had seven mice and each mouse bearing one tumor.

FIG. 3 is a line graph showing in vivo antitumor activity of Cpd. No. 4and Cpd. No. 6 in the RS4;11 ALL cancer xenograft model in SCID mice.Drug was administered I.V., three times per week at 25 mg/kg for 2 weeksor via oral gavage, five times per week at 50 mg/kg for 2 weeks. Eachgroup had five mice with each mouse bearing one tumor.

FIG. 4 is a Kaplan-Meier survival graph showing in vivo antitumoractivity of Cpd. No. 6 in the RS4;11 bone marrow engraftment model inNOD-SCID mice. Drug was administered at route and schedule indicated.Each group had 9-10 mice. P-values were determined using Mantel-CoxLog-rank test.

FIG. 5 is a Kaplan-Meier survival graph showing in vivo antitumoractivity of Cpd. No. 4 and Cpd. No. 6 in the RS4;11 bone marrowengraftment model in NOD-SCID mice. Drug was administered at route andschedule indicated. Each group had 9 or 10 mice. P-values weredetermined using Mantel-Cox Log-rank test.

FIG. 6 is an illustration of a Western blot showing the MDM2, p53, andGAPDH protein levels in RS4;11 cells after treatment with Cpd. B, Cpd.C, Cpd. No. 4, and Cpd. No. 6 for 2 hours.

FIG. 7 is an illustration of a Western blot showing the MDM2, p53, andGAPDH protein levels in 22RV1 cells after treatment with Cpd. A, Cpd.No. 4, and Cpd. D for two hours.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Disclosure

Compounds of the Disclosure are heterobifunctional compounds thatpromote MDM2 degradation. In one embodiment, Compounds of the Disclosureare compounds represented by Formula I:

wherein:

R^(1a) and R^(1b) are independently selected from the group consistingof hydrogen, fluoro, and chloro;

R^(2a) and R^(2b) are independently selected from the group consistingof hydrogen, fluoro, and chloro;

R^(3a) is —CH₂C(CH₃)₃;

R^(3b) is hydrogen; or

R^(3a) and R^(3b) taken together with the carbon atom to which they areattached form a cyclobutyl, cyclopentyl, or cyclohexyl group that isunsubstituted or substituted with one or two methyl groups;

R⁴ is selected from the group consisting of hydrogen, methyl, and ethyl;

X is selected from the group consisting of:

wherein the bond projecting to the right is attached to —C(═O)—Y-L-Z-A;

each R⁵ is independently selected from the group consisting of hydrogenand methyl;

R⁶ is selected from the group consisting of hydrogen, fluoro, chloro,methyl, and methoxy;

Y is selected from the group consisting of:

wherein the bond projecting to the right is attached to -L-Z-A;

R⁷ is selected from the group consisting of hydrogen, hydroxy, andmethyl;

L is selected from the group consisting of —(CH₂)_(m) and—(CH₂CH₂O)_(n)—

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

n is 2, 3, 4, 5, or 6;

Z is selected from the group consisting of —C≡C—, —NH—, —O—, and

or

Z is absent;

A is selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) is —CH₂C(CH₃)₃ and R^(3b) ishydrogen, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) and R^(3b) taken together withthe carbon atom to which they are attached form an cyclohexyl group thatis unsubstituted, or a pharmaceutically acceptable salt or solvatethereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) and R^(3b) taken together withthe carbon atom to which they are attached form a cyclohexyl group thatis unsubstituted or a pharmaceutically acceptable salt or solvatethereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) and R^(3b) taken together withthe carbon atom to which they are attached form a cyclobutyl group thatis unsubstituted or a pharmaceutically acceptable salt or solvatethereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) and R^(3b) taken together withthe carbon atom to which they are attached form a 3,3-dimethylcyclobutylgroup or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) and R^(3b) taken together withthe carbon atom to which they are attached form a cyclopentyl group thatis unsubstituted or a pharmaceutically acceptable salt or solvatethereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) and R^(3b) taken together withthe carbon atom to which they are attached form a cyclohexyl group thatis substituted with one or two methyl groups, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein R^(3a) and R^(3b) taken together withthe carbon atom to which they are attached form a 4,4-dimethylcyclohexylgroup or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Y is —N(H)—, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Y is Y-2, or a pharmaceuticallyacceptable salt or solvate thereof. In another embodiment, R⁷ ishydrogen. In another embodiment R⁷ is methyl.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Y is Y-3, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein L is —(CH₂)_(m)—, or apharmaceutically acceptable salt or solvate thereof. In anotherembodiment, m is 0, 1, 2, or 3. In another embodiment, m is 0.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein L is —(CH₂CH₂O)_(n)—, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Z is —C≡C—, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Z is

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Z is —NH—, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Z is —O—, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein Z is absent, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein A is A-1, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein A is A-2, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein A is A-3, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein A is A-4, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, wherein A is A-5, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula II:

or a pharmaceutically acceptable salt or solvate thereof, whereinR^(2a), R^(2b), R⁴, and X are as defined in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein R^(2a) is selected from thegroup consisting of fluoro and chloro, or a pharmaceutically acceptablesalt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein R^(2b) is selected from thegroup consisting of fluoro and chloro, or a pharmaceutically acceptablesalt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein R⁴ is hydrogen.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein R⁴ is methyl.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-1, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-2, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-3, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-4, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-5, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-6, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-7, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-8, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-9, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-10, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein X is X-11, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein R⁵ is hydrogen, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formulae I or II, wherein R⁵ is methyl, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are any one or moreof the compounds of Table 1, and the pharmaceutically acceptable saltsand solvates thereof.

In another embodiment, Compounds of the Disclosure are any one or bothof the compounds of Table 1A, and the pharmaceutically acceptable saltsand solvates thereof.

Table 1B provides the chemical names of the compounds of Tables 1 and 1Agenerated by Chemdraw® Professional version 17.0.0.206. In the event ofany ambiguity between their chemical structure and chemical name,Compounds of the Disclosure are defined by their chemical structure.

TABLE 1 Cpd. No. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

TABLE 1A Cpd. No. Structure 37

38

TABLE 1B Cpd. No. Name 1(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-((3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)propyl)carbamoyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide2 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)carbamoyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 3(2′S,3R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)carbamoyl)cyclohexyl)-2′-neopentyl-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide 4(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide5 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(1-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide6 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 73-(4-((1-(2-(4-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carbonyl)piperazin-1-yl)acetyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(1-(2-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)amino)-2-oxoethyl)piperidin-4-yl)-4,4-dimethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide9 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-1′-methyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide10 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-1 ′-methyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide11 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[1.1.1]pentan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 12(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,3R)-3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclobutyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide13 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-4,4-dimethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- 14(3′R,4′S,5′R)-6″-chloro-4′-(2,3-difluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 15(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-N-methyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide16 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-N,1′-dimethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide17 (3′R,4′S,5′R)-6″-chloro-4′-(2,3-difluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide18 (3′R,4′S,5′R)-4′-(2,3-difluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-6″-fluoro-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide19 (3′R,4′S,5′R)-4′-(2,3-difluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-6″-fluoro-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 20(2′S,3R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-2′-neopentyl-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide 21(2′S,3R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2′-neopentyl-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide 223-(4-((1-(1-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 233-(4-((1-(1-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 24(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)phenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 25(3′R,4′S,5′R)-6″-chloro-N-(4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)carbamoyl)cyclohexyl)-4′-(2-fluorophenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 26(3′R,4′R,5′R)-6″-chloro-4′-(3-chlorophenyl)-N-((1r,4R)-4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)carbamoyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 27(3′R,4′R,5′R)-6″-chloro-N-((1r,4R)-4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)carbamoyl)cyclohexyl)-2″-oxo-4′-phenyldispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 28(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)-2-methoxyphenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 293-(4-((1-(2-(1-((3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carbonyl)piperidin-4-yl)acetyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 30(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)-4-methylpiperidine-1-carbonyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide31 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)-4-methylpiperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide32 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)azetidine-1-carbonyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 33(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)azetidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro [cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 34(3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-((10-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-10-oxodecyl)carbamoyl)phenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide35 (3′R,4′S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(((S)-17-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbonyl)-18,18-dimethyl-15-oxo-3,6,9,12-tetraoxa-16-azanonadecyl)carbamoyl)phenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′- carboxamide36 (3′R,4′S,5′R)-N-(4-(((S)-1-((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidin-2-yl)-3-(4-(4-methylthiazol-5-yl)phenyl)-1,5-dioxo-9,12,15-trioxa-2,6-diazaheptadecan-17-yl)carbamoyl)phenyl)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide 372-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)-N-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-yn-1-yl)acetamide 38(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2[octan-1-yl)-5-neopentylpyrrolidine-2- carboxamide

In another embodiment, the disclosure provides a pharmaceuticalcomposition comprising a Compound of the Disclosure and apharmaceutically acceptable carrier.

Compounds of the Disclosure are heterobifunctional molecules. In oneembodiment, the spiro-oxindole portion of the molecule, i.e.,

is enantiomerically enriched, e.g., the enantiomeric excess or “ee” ofthis part of the heterobifunctional compound is about 5% or more asmeasured by chiral HPLC. In another embodiment, the ee is about 10%. Inanother embodiment, the ee is about 20%. In another embodiment, the eeis about 30%. In another embodiment, the ee is about 40%. In anotherembodiment, the ee is about 50%. In another embodiment, the ee is about60%. In another embodiment, the ee is about 70%. In another embodiment,the ee is about 80%. In another embodiment, the ee is about 85%. Inanother embodiment, the ee is about 90%. In another embodiment, the eeis about 91%. In another embodiment, the ee is about 92%. In anotherembodiment, the ee is about 93%. In another embodiment, the ee is about94%. In another embodiment, the ee is about 95%. In another embodiment,the ee is about 96%. In another embodiment, the ee is about 97%. Inanother embodiment, the ee is about 98%. In another embodiment, the eeis about 99%.

In another embodiment, the cereblon binding portion of the molecule,i.e., -A, is enantiomerically enriched. In another embodiment, thecereblon binding portion of the molecule is racemic. The presentdisclosure encompasses all possible stereoisomeric, e.g.,diastereomeric, forms of Compounds of the Disclosure. For example, allpossible stereoisomers of Compounds of the Disclosure are encompassedwhen the spiro-oxindole portion of the molecule is entantiomericallyenriched and the cereblon binding portion of the molecule is racemic.

The present disclosure encompasses the preparation and use of salts ofCompounds of the Disclosure. As used herein, the pharmaceutical“pharmaceutically acceptable salt” refers to salts or zwitterionic formsof Compounds of the Disclosure. Salts of Compounds of the Disclosure canbe prepared during the final isolation and purification of the compoundsor separately by reacting the compound with a suitable acid. Thepharmaceutically acceptable salts of Compounds of the Disclosure can beacid addition salts formed with pharmaceutically acceptable acids.Examples of acids which can be employed to form pharmaceuticallyacceptable salts include inorganic acids such as nitric, boric,hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acidssuch as oxalic, maleic, succinic, and citric. Non-limiting examples ofsalts of compounds of the disclosure include, but are not limited to,the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate,2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate,adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerolphsphate, hemisulfate,heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate,isethionate, salicylate, methanesulfonate, mesitylenesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate,propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate,bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate,tartrate, gluconate, methanesulfonate, ethanedisulfonate (edisylate),benzene sulfonate, p-toluenesulfonate, and naphthalene-1,5-disulfonatesalts. In addition, available amino groups present in the compounds ofthe disclosure can be quaternized with methyl, ethyl, propyl, and butylchlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamylsulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, andiodides; and benzyl and phenethyl bromides. In light of the foregoing,any reference Compounds of the Disclosure appearing herein is intendedto include compounds of Compounds of the Disclosure as well aspharmaceutically acceptable salts, hydrates, or solvates thereof.

In one embodiment, salts of Compounds of the Disclosure are preparedfrom any of the following acids: HCl, H₂SO₄, p-toluenesulfonic acid,methanesulfonic acid, benzenesulfonic acid, L-aspartic acid, maleicacid, H₃PO₄, L-glutamic acid, malonic acid, L-tartaric acid, fumaricacid, citric acid, lactobionic acid, glycolic acid, L-malic acid,gluconic acid, DL-lactic acid, succinic acid, or acetic acid.

In another embodiment, salts of Compounds of the Disclosure are preparedfrom any of the following acids: hydrobromic acid, dichloroacetic acid,camphor sulfonic acid, ethane-1,2-disulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, or oxalicacid. In another embodiment, salts of Compounds of the Disclosure areprepared from ethane-1,2-disulfonic acid or naphthalene-1,5-disulfonicacid.

In another embodiment, the Compounds of the Disclosure are selected fromthe group consisting of:

(1) the ethane-1,2-disulfonic acid salt of(3′R,4'S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide;

(2) the ethane-1,2-disulfonic acid salt of(3′R,4'S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide;

(3) the naphthalene-1,5-disulfonic acid salt of(3′R,4'S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide;and

(4) the naphthalene-1,5-disulfonic acid salt of(3′R,4'S,5′R)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-N-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)bicyclo[2.2.2]octan-1-yl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide.

The present disclosure encompasses the preparation and use of solvatesof Compounds of the Disclosure. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present disclosure with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present disclosure is about 2:1, about 1:1or about 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of the Disclosure can be present assolvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, and ethanol, and it is intended that the disclosureincludes both solvated and unsolvated forms of Compounds of theDisclosure. One type of solvate is a hydrate. A “hydrate” relates to aparticular subgroup of solvates where the solvent molecule is water.Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a Compound of the Disclosure in a desired solvent(organic, water, or a mixture thereof), e.g., at temperature above 20°C., then cooling the solution at a rate sufficient to form crystals, andisolating the crystals by known methods, e.g., filtration. Analyticaltechniques such as infrared spectroscopy can be used to confirm thepresence of the solvent in a crystal of the solvate.

II. Therapeutic Methods of the Disclosure

Compounds of the Disclosure degrade MDM2 proteins and are useful in thetreatment of a variety of diseases and conditions. In particular,Compounds of the Disclosure are useful in methods of treating a diseaseor condition wherein degradation MDM2 proteins provides a benefit, forexample, cancers and proliferative diseases. The therapeutic methods ofthe disclosure comprise administering a therapeutically effective amountof a Compound of the Disclosure to an individual in need thereof. Thepresent methods also encompass administering a second therapeutic agentto the individual in addition to the Compound of the Disclosure. Thesecond therapeutic agent is selected from drugs known as useful intreating the disease or condition afflicting the individual in needthereof, e.g., a chemotherapeutic agent and/or radiation known as usefulin treating a particular cancer.

The present disclosure provides Compounds of the Disclosure as MDM2protein degraders for the treatment of a variety of diseases andconditions wherein degradation of MDM2 proteins has a beneficial effect.Compounds of the Disclosure typically have a binding affinity (IC₅₀) toMDM2 of less than 100 μM, e.g., less than 50 μM, less than M, and lessthan 5 μM, less than about 1 μM, less than about 0.5 μM, or less thanabout 0.1 μM. In one embodiment, the present disclosure relates to amethod of treating an individual suffering from a disease or conditionwherein degradation of MDM2 proteins provides a benefit comprisingadministering a therapeutically effective amount of a Compound of theDisclosure to an individual in need thereof.

Since Compounds of the Disclosure are degraders of MDM2 protein, anumber of diseases and conditions mediated by MDM2 can be treated byemploying these compounds. The present disclosure is thus directedgenerally to a method for treating a condition or disorder responsive todegradation of MDM2 in an animal, e.g., a human, suffering from, or atrisk of suffering from, the condition or disorder, the method comprisingadministering to the animal an effective amount of one or more Compoundsof the Disclosure.

The present disclosure is further directed to a method of degrading MDM2protein in an animal in need thereof, said method comprisingadministering to the animal an effective amount of at least one Compoundof the Disclosure.

The methods of the present disclosure can be accomplished byadministering a Compound of the Disclosure as the neat compound or as apharmaceutical composition. Administration of a pharmaceuticalcomposition, or neat compound of a Compound of the Disclosure, can beperformed during or after the onset of the disease or condition ofinterest. Typically, the pharmaceutical compositions are sterile, andcontain no toxic, carcinogenic, or mutagenic compounds that would causean adverse reaction when administered. Further provided are kitscomprising a Compound of the Disclosure and, optionally, a secondtherapeutic agent useful in the treatment of diseases and conditionswherein degradation of MDM2 protein provides a benefit, packagedseparately or together, and an insert having instructions for usingthese active agents.

In one embodiment, a Compound of the Disclosure is administered inconjunction with a second therapeutic agent useful in the treatment of adisease or condition wherein degradation of MDM2 protein provides abenefit. The second therapeutic agent is different from the Compound ofthe Disclosure. A Compound of the Disclosure and the second therapeuticagent can be administered simultaneously or sequentially to achieve thedesired effect. In addition, the Compound of the Disclosure and secondtherapeutic agent can be administered from a single composition or twoseparate compositions.

The second therapeutic agent is administered in an amount to provide itsdesired therapeutic effect. The effective dosage range for each secondtherapeutic agent is known in the art, and the second therapeutic agentis administered to an individual in need thereof within such establishedranges.

A Compound of the Disclosure and the second therapeutic agent can beadministered together as a single-unit dose or separately as multi-unitdoses, wherein the Compound of the Disclosure is administered before thesecond therapeutic agent or vice versa. One or more doses of theCompound of the Disclosure and/or one or more dose of the secondtherapeutic agent can be administered. The Compound of the Disclosuretherefore can be used in conjunction with one or more second therapeuticagents, for example, but not limited to, anticancer agents.

Diseases and conditions treatable by the methods of the presentdisclosure include, but are not limited to, cancer and otherproliferative disorders, inflammatory diseases, sepsis, autoimmunedisease, and viral infection. In one embodiment, a human patient istreated with a Compound of the Disclosure, or a pharmaceuticalcomposition comprising a Compound of the Disclosure, wherein thecompound is administered in an amount sufficient to degrade MDM2 proteinin the patient.

In another aspect, the present disclosure provides a method of treatingcancer in a subject comprising administering a therapeutically effectiveamount of a Compound of the Disclosure. While not being limited to aspecific mechanism, in some embodiments, Compounds of the Disclosuretreat cancer by degrading MDM2 protein. Examples of treatable cancersinclude, but are not limited to, the cancers listed in Table 2.

TABLE 2 adrenal cancer acinic cell carcinoma acoustic neuroma acrallentigious melanoma acrospiroma acute eosinophilic acute erythroid acutelymphoblastic leukemia leukemia leukemia acute acute monocytic acutepromyelocytic adenocarcinoma megakaryoblastic leukemia leukemia leukemiaadenoid cystic adenoma adenomatoid adenosquamous carcinoma odontogenictumor carcinoma adipose tissue adrenocortical adult T-cell aggressiveNK-cell neoplasm carcinoma leukemia/lymphoma leukemia AIDS-relatedalveolar alveolar soft part ameloblastic lymphoma rhabdomyosarcomasarcoma fibroma anaplastic large cell anaplastic thyroidangioimmunoblastic angiomyolipoma lymphoma cancer T-cell lymphomaangiosarcoma astrocytoma atypical teratoid B-cell chronic rhabdoid tumorlymphocytic leukemia B-cell B-cell lymphoma basal cell carcinoma biliarytract cancer prolymphocytic leukemia bladder cancer blastoma bone cancerBrenner tumor Brown tumor Burkitt's lymphoma breast cancer brain cancercarcinoma carcinoma in situ carcinosarcoma cartilage tumor cementomamyeloid sarcoma chondroma chordoma choriocarcinoma choroid plexusclear-cell sarcoma of craniopharyngioma papilloma the kidney cutaneousT-cell cervical cancer colorectal cancer Degos disease lymphomadesmoplastic small diffuse large B-cell dysembryoplastic dysgerminomaround cell tumor lymphoma neuroepithelial tumor embryonal endocrinegland endodermal sinus enteropathy- carcinoma neoplasm tumor associatedT-cell lymphoma esophageal cancer fetus in fetu fibroma fibrosarcomafollicular follicular thyroid ganglioneuroma gastrointestinal lymphomacancer cancer germ cell tumor gestational giant cell giant cell tumor ofchoriocarcinoma fibroblastoma the bone glial tumor glioblastoma gliomagliomatosis cerebri multiforme glucagonoma gonadoblastoma granulosa celltumor gynandroblastoma gallbladder cancer gastric cancer hairy cellleukemia hemangioblastoma head and neck hemangiopericytoma hematologicalhepatoblastoma cancer cancer hepatosplenic T-cell Hodgkin'snon-Hodgkin's invasive lobular lymphoma lymphoma lymphoma carcinomaintestinal cancer kidney cancer laryngeal cancer lentigo maligna lethalmidline leukemia leydig cell tumor liposarcoma carcinoma lung cancerlymphangioma lymphangiosarcoma lymphoepithelioma lymphoma acutelymphocytic acute myelogeous chronic leukemia leukemia lymphocyticleukemia liver cancer small cell lung non-small cell lung MALT lymphomacancer cancer malignant fibrous malignant peripheral malignant tritonmantle cell histiocytoma nerve sheath tumor tumor lymphoma marginal zoneB- mast cell leukemia mediastinal germ medullary cell lymphoma celltumor carcinoma of the breast medullary thyroid medulloblastoma melanomameningioma cancer merkel cell cancer mesothelioma metastatic urothelialmixed Mullerian carcinoma tumor mucinous tumor multiple myeloma muscletissue mycosis fungoides neoplasm myxoid myxoma myxosarcomanasopharyngeal liposarcoma carcinoma neurinoma neuroblastomaneurofibroma neuroma nodular melanoma ocular cancer oligoastrocytomaoligodendroglioma oncocytoma optic nerve sheath optic nerve tumor oralcancer meningioma osteosarcoma ovarian cancer Pancoast tumor papillarythyroid cancer paraganglioma pinealoblastoma pineocytoma pituicytomapituitary adenoma pituitary tumor plasmacytoma polyembryoma precursor T-primary central primary effusion preimary peritoneal lymphoblasticnervous system lymphoma cancer lymphoma lymphoma prostate cancerpancreatic cancer pharyngeal cancer pseudomyxoma periotonei renal cellcarcinoma renal medullary retinoblastoma rhabdomyoma carcinomarhabdomyosarcoma Richter's rectal cancer sarcoma transformationSchwannomatosis seminoma Sertoli cell tumor sex cord-gonadal stromaltumor signet ring cell skin cancer small blue round cell small cellcarcinoma tumors carcinoma soft tissue sarcoma somatostatinoma soot wartspinal tumor splenic marginal squamous cell synovial sarcoma Sezary'sdisease zone lymphoma carcinoma small intestine squamous carcinomastomach cancer T-cell lymphoma cancer testicular cancer thecoma thyroidcancer transitional cell carcinoma throat cancer urachal cancerurogenital cancer urothelial carcinoma uveal melanoma uterine cancerverrucous carcinoma visual pathway glioma vulvar cancer vaginal cancerWaldenstrom's Warthin's tumor macroglobulinemia Wilms' tumor

In another embodiment, the cancer is a solid tumor. In anotherembodiment, the cancer a hematological cancer. Exemplary hematologicalcancers include, but are not limited to, the cancers listed in Table 3.In another embodiment, the hematological cancer is acute lymphocyticleukemia, chronic lymphocytic leukemia (including B-cell chroniclymphocytic leukemia), or acute myeloid leukemia.

TABLE 3 acute lymphocytic leukemia (ALL) acute eosinophilic leukemiaacute myeloid leukemia (AML) acute erythroid leukemia chroniclymphocytic leukemia (CLL) acute lymphoblastic leukemia smalllymphocytic lymphoma (SLL) acute megakaryoblastic leukemia multiplemyeloma (MM) acute monocytic leukemia Hodgkins lymphoma (HL) acutepromyelocytic leukemia non-Hodgkin's lymphoma (NHL) acute myelogeousleukemia mantle cell lymphoma (MCL) B-cell prolymphocytic leukemiamarginal zone B-cell lymphoma B-cell lymphoma splenic marginal zonelymphoma MALT lymphoma follicular lymphoma (FL) precursorT-lymphoblastic Waldenstrom's macroglobulinemia lymphoma (WM) T-celllymphoma diffuse large B-cell lymphoma mast cell leukemia (DLBCL) adultT cell leukemia/lymphoma marginal zone lymphoma (MZL) aggressive NK-cellleukemia hairy cell leukemia (HCL) angioimmunoblastic T-cell Burkitt'slymphoma (BL) lymphoma Richter's transformation

In methods of the present disclosure, a therapeutically effective amountof a Compound of the Disclosure, typically formulated in accordance withpharmaceutical practice, is administered to a human being in needthereof. Whether such a treatment is indicated depends on the individualcase and is subject to medical assessment (diagnosis) that takes intoconsideration signs, symptoms, and/or malfunctions that are present, therisks of developing particular signs, symptoms and/or malfunctions, andother factors.

A Compound of the Disclosure can be administered by any suitable route,for example by oral, buccal, inhalation, sublingual, rectal, vaginal,intracisternal or intrathecal through lumbar puncture, transurethral,nasal, percutaneous, i.e., transdermal, or parenteral (includingintravenous, intramuscular, subcutaneous, intracoronary, intradermal,intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar,intrapulmonary injection and/or surgical implantation at a particularsite) administration. Parenteral administration can be accomplishedusing a needle and syringe or using a high pressure technique.

Pharmaceutical compositions include those wherein a Compound of theDisclosure is administered in an effective amount to achieve itsintended purpose. The exact formulation, route of administration, anddosage is determined by an individual physician in view of the diagnosedcondition or disease. Dosage amount and interval can be adjustedindividually to provide levels of a Compound of the Disclosure that issufficient to maintain therapeutic effects.

Toxicity and therapeutic efficacy of the Compounds of the Disclosure canbe determined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the maximum tolerated dose(MTD) of a compound, which defines as the highest dose that causes notoxicity in animals. The dose ratio between the maximum tolerated doseand therapeutic effects (e.g. inhibiting of tumor growth) is thetherapeutic index. The dosage can vary within this range depending uponthe dosage form employed, and the route of administration utilized.Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

A therapeutically effective amount of a Compound of the Disclosurerequired for use in therapy varies with the nature of the conditionbeing treated, the length of time that activity is desired, and the ageand the condition of the patient, and ultimately is determined by theattendant physician. Dosage amounts and intervals can be adjustedindividually to provide plasma levels of the MDM2 protein degrader thatare sufficient to maintain the desired therapeutic effects. The desireddose conveniently can be administered in a single dose, or as multipledoses administered at appropriate intervals, for example as one, two,three, four or more subdoses per day. Multiple doses often are desired,or required. For example, a Compound of the Disclosure can beadministered at a frequency of: four doses delivered as one dose per dayat four-day intervals (q4d×4); four doses delivered as one dose per dayat three-day intervals (q3d×4); one dose delivered per day at five-dayintervals (qd×5); one dose per week for three weeks (qwk3); five dailydoses, with two days rest, and another five daily doses (5/2/5); or, anydose regimen determined to be appropriate for the circumstance.

A Compound of the Disclosure used in a method of the present disclosurecan be administered in an amount of about 0.005 to about 500 milligramsper dose, about 0.05 to about 250 milligrams per dose, or about 0.5 toabout 100 milligrams per dose. For example, a Compound of the Disclosurecan be administered, per dose, in an amount of about 0.005, 0.05, 0.5,5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500milligrams, including all doses between 0.005 and 500 milligrams.

The dosage of a composition containing a Compound of the Disclosure, ora composition containing the same, can be from about 1 ng/kg to about200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about50 mg/kg. The dosage of a composition can be at any dosage including,but not limited to, about 1 μg/kg. The dosage of a composition may be atany dosage including, but not limited to, about 1 μg/kg, about 10 μg/kg,about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925μg/kg, about 950 μg/kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg,about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg,about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200mg/kg, or more. The above dosages are exemplary of the average case, butthere can be individual instances in which higher or lower dosages aremerited, and such are within the scope of this disclosure. In practice,the physician determines the actual dosing regimen that is most suitablefor an individual patient, which can vary with the age, weight, andresponse of the particular patient.

A Compound of the Disclosure can be administered in combination with asecond therapeutically active agent. In some embodiments, the secondtherapeutic agent is an epigenetic drug. As used herein, the term“epigenetic drug” refers to a therapeutic agent that targets anepigenetic regulator. Examples of epigenetic regulators include thehistone lysine methyltransferases, histone arginine methyl transferases,histone demethylases, histone deacetylases, histone acetylases, and DNAmethyltransferases. Histone deacetylase inhibitors include, but are notlimited to, vorinostat.

In another embodiment, chemotherapeutic agents or otheranti-proliferative agents can be combined with Compound of theDisclosure to treat proliferative diseases and cancer. Examples oftherapies and anticancer agents that can be used in combination withCompounds of the Disclosure include surgery, radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes),endocrine therapy, a biologic response modifier (e.g., an interferon, aninterleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy,an agent to attenuate any adverse effect (e.g., an antiemetic), and anyother approved chemotherapeutic drug.

Examples of antiproliferative compounds include, but are not limited to,an aromatase inhibitor; an anti-estrogen; an anti-androgen; agonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase IIinhibitor; a microtubule active agent; an alkylating agent; a retinoid,a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMPinhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; amethionine aminopeptidase inhibitor; a bisphosphonate; anantiproliferative antibody; a heparanase inhibitor; an inhibitor of Rasoncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; acompound used in the treatment of hematologic malignancies; a Flt-3inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; aMEK inhibitor; an antitumor antibiotic; a nitrosourea; a compoundtargeting/decreasing protein or lipid kinase activity, a compoundtargeting/decreasing protein or lipid phosphatase activity, or anyfurther anti-angiogenic compound.

Non-limiting exemplary aromatase inhibitors include, but are not limitedto, steroids, such as atamestane, exemestane, and formestane, andnon-steroids, such as aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole, and letrozole.

Non-limiting anti-estrogens include, but are not limited to, tamoxifen,fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgensinclude, but are not limited to, bicalutamide. Gonadorelin agonistsinclude, but are not limited to, abarelix, goserelin, and goserelinacetate.

Exemplary topoisomerase I inhibitors include, but are not limited to,topotecan, gimatecan, irinotecan, camptothecin and its analogues,9-nitrocamptothecin, and the macromolecular camptothecin conjugatePNU-166148. Topoisomerase II inhibitors include, but are not limited to,anthracyclines, such as doxorubicin, daunorubicin, epirubicin,idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone andlosoxantrone; and podophillotoxines, such as etoposide and teniposide.

Microtubule active agents include microtubule stabilizing, microtubuledestabilizing compounds, and microtubulin polymerization inhibitorsincluding, but not limited to, taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate,vincristine, and vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof.

Exemplary non-limiting alkylating agents include cyclophosphamide,ifosfamide, melphalan, and nitrosoureas, such as carmustine andlomustine.

Exemplary non-limiting cyclooxygenase inhibitors include Cox-2inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid andderivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.

Exemplary non-limiting matrix metalloproteinase inhibitors (“MMPinhibitors”) include collagen peptidomimetic and nonpeptidomimeticinhibitors, tetracycline derivatives, batimastat, marimastat,prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, andAAJ996.

Exemplary non-limiting mTOR inhibitors include compounds that inhibitthe mammalian target of rapamycin (mTOR) and possess antiproliferativeactivity such as sirolimus, everolimus, CCI-779, and ABT578.

Exemplary non-limiting antimetabolites include 5-fluorouracil (5-FU),capecitabine, gemcitabine, DNA demethylating compounds, such as5-azacytidine and decitabine, methotrexate and edatrexate, and folicacid antagonists, such as pemetrexed.

Exemplary non-limiting platin compounds include carboplatin, cis-platin,cisplatinum, and oxaliplatin.

Exemplary non-limiting methionine aminopeptidase inhibitors includebengamide or a derivative thereof and PPI-2458.

Exemplary non-limiting bisphosphonates include etridonic acid, clodronicacid, tiludronic acid, pamidronic acid, alendronic acid, ibandronicacid, risedronic acid, and zoledronic acid.

Exemplary non-limiting antiproliferative antibodies include trastuzumab,trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4.The term “antibody” includes intact monoclonal antibodies, polyclonalantibodies, multispecific antibodies formed from at least two intactantibodies, and antibody fragments, so long as they exhibit the desiredbiological activity.

Exemplary non-limiting heparanase inhibitors include compounds thattarget, decrease, or inhibit heparin sulfate degradation, such as PI-88and OGT2115.

The term “an inhibitor of Ras oncogenic isoforms,” such as H-Ras, K-Ras,or N-Ras, as used herein refers to a compound which targets, decreases,or inhibits the oncogenic activity of Ras, for example, a farnesyltransferase inhibitor, such as L-744832, DK8G557, tipifarnib, andlonafarnib.

Exemplary non-limiting telomerase inhibitors include compounds thattarget, decrease, or inhibit the activity of telomerase, such ascompounds that inhibit the telomerase receptor, such as telomestatin.

Exemplary non-limiting proteasome inhibitors include compounds thattarget, decrease, or inhibit the activity of the proteasome including,but not limited to, bortezomid.

The phrase “compounds used in the treatment of hematologic malignancies”as used herein includes FMS-like tyrosine kinase inhibitors, which arecompounds targeting, decreasing or inhibiting the activity of FMS-liketyrosine kinase receptors (Flt-3R); interferon,I-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors,which are compounds which target, decrease, or inhibit anaplasticlymphoma kinase.

Exemplary non-limiting Flt-3 inhibitors include PKC412, midostaurin, astaurosporine derivative, SU11248, and MLN518.

Exemplary non-limiting HSP90 inhibitors include compounds targeting,decreasing, or inhibiting the intrinsic ATPase activity of HSP90; ordegrading, targeting, decreasing or inhibiting the HSP90 client proteinsvia the ubiquitin proteosome pathway. Compounds targeting, decreasing orinhibiting the intrinsic ATPase activity of HSP90 are especiallycompounds, proteins, or antibodies that inhibit the ATPase activity ofHSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), ageldanamycin derivative; other geldanamycin related compounds; radicicoland HDAC inhibitors.

The phrase “a compound targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or any furtheranti-angiogenic compound” as used herein includes a protein tyrosinekinase and/or serine and/or threonine kinase inhibitor or lipid kinaseinhibitor, such as a) a compound targeting, decreasing, or inhibitingthe activity of the platelet-derived growth factor-receptors (PDGFR),such as a compound that targets, decreases, or inhibits the activity ofPDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such asimatinib, SUlOl, SU6668, and GFB-111; b) a compound targeting,decreasing, or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) a compound targeting, decreasing, orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as a compound that targets, decreases, or inhibits theactivity of IGF-IR; d) a compound targeting, decreasing, or inhibitingthe activity of the Trk receptor tyrosine kinase family, or ephrin B4inhibitors; e) a compound targeting, decreasing, or inhibiting theactivity of the Axl receptor tyrosine kinase family; f) a compoundtargeting, decreasing, or inhibiting the activity of the Ret receptortyrosine kinase; g) a compound targeting, decreasing, or inhibiting theactivity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h)a compound targeting, decreasing, or inhibiting the activity of thec-Kit receptor tyrosine kinases, such as imatinib; i) a compoundtargeting, decreasing, or inhibiting the activity of members of thec-Abl family, their gene-fusion products (e.g. Bcr-Abl kinase) andmutants, such as an N-phenyl-2-pyrimidine-amine derivative, such asimatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; ordasatinib; j) a compound targeting, decreasing, or inhibiting theactivity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1,PKB/Akt, and Ras/MAPK family members, and/or members of thecyclin-dependent kinase family (CDK), such as a staurosporine derivativedisclosed in U.S. Pat. No. 5,093,330, such as midostaurin; examples offurther compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1,perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; a isochinoline compound; a farnesyl transferaseinhibitor; PD184352 or QAN697, or AT7519; k) a compound targeting,decreasing or inhibiting the activity of a protein-tyrosine kinase, suchas imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG-50810;AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490;Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG494; Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) a compound targeting, decreasing, orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180;trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, C1-1033, EKB-569,GW-2016, antibodies EL.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 andE7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) a compoundtargeting, decreasing, or inhibiting the activity of the c-Met receptor.

Exemplary compounds that target, decrease, or inhibit the activity of aprotein or lipid phosphatase include inhibitors of phosphatase 1,phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity unrelated to protein or lipid kinaseinhibition, e.g., thalidomide and TNP-470.

Additional, nonlimiting, exemplary chemotherapeutic compounds, one ormore of which may be used in combination with a present MDM2 degrader,include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide,mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine(6-MP), fludarabine phosphate, octreotide, SOM230, FTY720,6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea,2-hydroxy-1H-isoindole-1,3-dione derivatives,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate,angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474,SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors,FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimersodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol,cortex olone, 17a-hydroxyprogesterone, corticosterone,desoxycorticosterone, testosterone, estrone, dexamethasone,fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, abiological response modifier, such as a lymphokine or interferon, anantisense oligonucleotide or oligonucleotide derivative, shRNA, andsiRNA.

Other examples of second therapeutic agents, one or more of which apresent MDM2 degrader also can be combined, include, but are not limitedto: a treatment for Alzheimer's Disease, such as donepezil andrivastigmine; a treatment for Parkinson's Disease, such asL-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine,pergolide, trihexephendyl, and amantadine; an agent for treatingmultiple sclerosis (MS) such as beta interferon (e.g., AVONEX® andREBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma,such as albuterol and montelukast; an agent for treating schizophrenia,such as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; animmunomodulatory agent, including immunosuppressive agents, such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, aninterferon, a corticosteroid, cyclophosphamide, azathioprine, andsulfasalazine; a neurotrophic factor, such as an acetylcholinesteraseinhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ionchannel blocker, riluzole, or an anti-Parkinson's agent; an agent fortreating cardiovascular disease, such as a beta-blocker, an ACEinhibitor, a diuretic, a nitrate, a calcium channel blocker, or astatin; an agent for treating liver disease, such as a corticosteroid,cholestyramine, an interferon, and an anti-viral agent; an agent fortreating blood disorders, such as a corticosteroid, an anti-leukemicagent, or a growth factor; or an agent for treating immunodeficiencydisorders, such as gamma globulin.

The above-mentioned second therapeutically active agents, one or more ofwhich can be used in combination with a Compound of the Disclosure, areprepared and administered as described in the art.

Compounds of the Disclosure typically are administered in admixture witha pharmaceutical carrier selected with regard to the intended route ofadministration and standard pharmaceutical practice. Pharmaceuticalcompositions for use in accordance with the present disclosure areformulated in a conventional manner using one or more physiologicallyacceptable carriers comprising excipients and/or auxiliaries thatfacilitate processing of Compound of the Disclosure.

These pharmaceutical compositions can be manufactured, for example, byconventional mixing, dissolving, granulating, dragee-making,emulsifying, encapsulating, entrapping, or lyophilizing processes.Proper formulation is dependent upon the route of administration chosen.When a therapeutically effective amount of the Compound of theDisclosure is administered orally, the composition typically is in theform of a tablet, capsule, powder, solution, or elixir. Whenadministered in tablet form, the composition additionally can contain asolid carrier, such as a gelatin or an adjuvant. The tablet, capsule,and powder contain about 0.01% to about 95%, and preferably from about1% to about 50%, of a Compound of the Disclosure. When administered inliquid form, a liquid carrier, such as water, petroleum, or oils ofanimal or plant origin, can be added. The liquid form of the compositioncan further contain physiological saline solution, dextrose or othersaccharide solutions, or glycols. When administered in liquid form, thecomposition contains about 0.1% to about 90%, and preferably about 1% toabout 50%, by weight, of a Compound of the Disclosure.

When a therapeutically effective amount of a Compound of the Disclosureis administered by intravenous, cutaneous, or subcutaneous injection,the composition is in the form of a pyrogen-free, parenterallyacceptable aqueous solution. The preparation of such parenterallyacceptable solutions, having due regard to pH, isotonicity, stability,and the like, is within the skill in the art. A preferred compositionfor intravenous, cutaneous, or subcutaneous injection typicallycontains, an isotonic vehicle.

Compounds of the Disclosure can be readily combined withpharmaceutically acceptable carriers well-known in the art. Standardpharmaceutical carriers are described in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 19th ed. 1995. Such carriersenable the active agents to be formulated as tablets, pills, dragees,capsules, liquids, gels, syrups, slurries, suspensions and the like, fororal ingestion by a patient to be treated. Pharmaceutical preparationsfor oral use can be obtained by adding the Compound of the Disclosure toa solid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate. Buffers and pH modifiers can also be added to stabilize thepharmaceutical composition.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Compound of the Disclosure can be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection can be presented in unit dosageform, e.g., in ampules or in multidose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing, and/or dispersingagents.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active agent in water-soluble form.Additionally, suspensions of a Compound of the Disclosure can beprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles include fatty oils or synthetic fatty acid esters.Aqueous injection suspensions can contain substances which increase theviscosity of the suspension. Optionally, the suspension also can containsuitable stabilizers or agents that increase the solubility of thecompounds and allow for the preparation of highly concentratedsolutions. Alternatively, a present composition can be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

Compounds of the Disclosure also can be formulated in rectalcompositions, such as suppositories or retention enemas, e.g.,containing conventional suppository bases. In addition to theformulations described previously, the Compound of the Disclosure alsocan be formulated as a depot preparation. Such long-acting formulationscan be administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, theCompound of the Disclosure can be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins.

In particular, the Compounds of the Disclosure can be administeredorally, buccally, or sublingually in the form of tablets containingexcipients, such as starch or lactose, or in capsules or ovules, eitheralone or in admixture with excipients, or in the form of elixirs orsuspensions containing flavoring or coloring agents. Such liquidpreparations can be prepared with pharmaceutically acceptable additives,such as suspending agents. Compound of the Disclosure also can beinjected parenterally, for example, intravenously, intramuscularly,subcutaneously, or intracoronarily. For parenteral administration, theCompound of the Disclosure are typically used in the form of a sterileaqueous solution which can contain other substances, for example, saltsor monosaccharides, such as mannitol or glucose, to make the solutionisotonic with blood.

The disclosure provides the following particular embodiments inconnection with treating a disease in a subject.

Embodiment 1. A method of treating a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount a Compound of the Disclosure, wherein the subject has cancer.

Embodiment 2. The method of Embodiment 1, wherein the cancer is any oneor more of the cancers of Table 2.

Embodiment 3. The method of Embodiment 2, wherein the cancer is ahematological cancer.

Embodiment 4. The method of Embodiment 3, wherein the hematologicalcancer is any one or more of the cancers of Table 3.

Embodiment 5. The method of any one of Embodiments 1-4 furthercomprising administering a therapeutically effective amount of a secondtherapeutic agent useful in the treatment of cancer.

Embodiment 6. A pharmaceutical composition comprising a Compound of theDisclosure and a pharmaceutically acceptable carrier for use in treatingcancer.

Embodiment 7. The pharmaceutical composition of Embodiment 6, whereinthe cancer is any one or more of the cancers of Table 2.

Embodiment 8. The pharmaceutical composition of Embodiment 7, whereinthe cancer is a hematological cancer.

Embodiment 9. The pharmaceutical composition of Embodiment 8, whereinthe hematological cancer is any one or more of the cancers of Table 3.

Embodiment 10. A Compound of the Disclosure for use in treatment ofcancer.

Embodiment 11. The compound for use of Embodiment 10, wherein the canceris any one or more of the cancers of Table 2.

Embodiment 12. The compound for use of Embodiment 11, wherein the canceris a hematological cancer.

Embodiment 13. The compound for use of Embodiment 12, wherein thehematological cancer is any one or more of the cancers of Table 3.

Embodiment 14. Use of a Compound of the Disclosure for the manufactureof a medicament for treatment of cancer.

Embodiment 15. The use of Embodiment 14, wherein the cancer is any oneor more of the cancers of Table 2.

Embodiment 16. The use of Embodiment 15, wherein the cancer is ahematological cancer.

Embodiment 17. The use of Embodiment 16, wherein the hematologicalcancer is any one or more of the cancers of Table 3.

III. Kits of the Disclosure

In another embodiment, the present disclosure provides kits whichcomprise a Compound of the Disclosure (or a composition comprising aCompound of the Disclosure) packaged in a manner that facilitates theiruse to practice methods of the present disclosure. In one embodiment,the kit includes a Compound of the Disclosure (or a compositioncomprising a Compound of the Disclosure) packaged in a container, suchas a sealed bottle or vessel, with a label affixed to the container orincluded in the kit that describes use of the compound or composition topractice the method of the disclosure. In one embodiment, the compoundor composition is packaged in a unit dosage form. The kit further caninclude a device suitable for administering the composition according tothe intended route of administration.

IV. Biomarkers

In another embodiment, present disclosure provides methods of treating asubject having cancer, comprising (a) determining whether a biobarker ispresent or absent in a biological sample taken from the subject; and (b)administering a therapeutically effective amount of a Compound of theDisclosure to the subject if the biomarker is present in the biologicalsample. See, e.g., Goossens et al., Transl Cancer Res. 4:256-269 (2015);Kamel and Al-Amodi, Genomics Proteomics Bioinformatics 15:220-235(2017); and Konikova and Kusenda, Neoplasma 50:31-40 (2003).

The term “biomarker” as used herein refers to any biological compound,such as a gene, a protein, a fragment of a protein, a peptide, apolypeptide, a nucleic acid, etc., that can be detected and/orquantified in a cancer patient in vivo or in a biological sampleobtained from a cancer patient. A biomarker can be the entire intactmolecule, or it can be a portion or fragment thereof. In one embodiment,the expression level of the biomarker is measured. The expression levelof the biomarker can be measured, for example, by detecting the proteinor RNA, e.g., mRNA, level of the biomarker. In some embodiments,portions or fragments of biomarkers can be detected or measured, forexample, by an antibody or other specific binding agent. In someembodiments, a measurable aspect of the biomarker is associated with agiven state of the patient, such as a particular stage of cancer. Forbiomarkers that are detected at the protein or RNA level, suchmeasurable aspects may include, for example, the presence, absence, orconcentration, i.e., expression level, of the biomarker in a cancerpatient, or biological sample obtained from the cancer patient. Forbiomarkers that are detected at the nucleic acid level, such measurableaspects may include, for example, allelic versions of the biomarker ortype, rate, and/or degree of mutation of the biomarker, also referred toherein as mutation status.

For biomarkers that are detected based on expression level of protein orRNA, expression level measured between different phenotypic statuses canbe considered different, for example, if the mean or median expressionlevel of the biomarker in the different groups is calculated to bestatistically significant. Common tests for statistical significanceinclude, among others, t-test, ANOVA, Kruskal-Wallis, Wilcoxon,Mann-Whitney, Significance Analysis of Microarrays, odds ratio, etc.Biomarkers, alone or in combination, provide measures of relativelikelihood that a subject belongs to one phenotypic status or another.Therefore, they are useful, inter alia, as markers for disease and asindicators that particular therapeutic treatment regimens will likelyresult in beneficial patient outcomes.

Biomarkers include, but are not limited to, MDM2, p53 and any one ormore of the other biomarkers disclosed in US 2015/0301058. In oneembodiment, the measurable aspect of the biomarker is its expressionstatus. In one embodiment, the measurable aspect of the biomarker is itsmutation status.

In one embodiment, the biomarker is MDM2 which is differentially presentin a subject of one phenotypic status, e.g., a subject having ahematological cancer, as compared with another phenotypic status, e.g.,a normal undiseased subject or a patient having cancer withoutoverexpression MDM2. In one embodiment, the biomarker is overexpressionof MDM2.

Biomarker standards can be predetermined, determined concurrently, ordetermined after a biological sample is obtained from the subject.Biomarker standards for use with the methods described herein can, forexample, include data from samples from subjects without cancer; datafrom samples from subjects with cancer, e.g., breast cancer, that is notmetastatic; and data from samples from subjects with cancer, e.g.,breast cancer, that metastatic. Comparisons can be made to establishpredetermined threshold biomarker standards for different classes ofsubjects, e.g., diseased vs. non-diseased subjects. The standards can berun in the same assay or can be known standards from a previous assay.

A biomarker is differentially present between different phenotypicstatus groups if the mean or median expression or mutation levels of thebiomarker is calculated to be different, i.e., higher or lower, betweenthe groups. Thus, biomarkers provide an indication that a subject, e.g.,a cancer patient, belongs to one phenotypic status or another.

In addition to individual biological compounds, e.g., MDM2, the term“biomarker” as used herein is meant to include groups, sets, or arraysof multiple biological compounds. For example, the combination of MDM2and p53 may comprise a biomarker. The term “biomarker” may comprise one,two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty,twenty five, thirty, or more, biological compounds.

The determination of the expression level or mutation status of abiomarker in a patient can be performed using any of the many methodsknown in the art. Any method known in the art for quantitating specificproteins and/or detecting MDM2 expression, or the expression or mutationlevels of any other biomarker in a patient or a biological sample may beused in the methods of the disclosure. Examples include, but are notlimited to, PCR (polymerase chain reaction), or RT-PCR, flow cytometry,Northern blot, Western blot, ELISA (enzyme linked immunosorbent assay),RIA (radioimmunoassay), gene chip analysis of RNA expression,immunohistochemistry or immunofluorescence. See, e.g., Slagle et al.Cancer 83:1401 (1998). Certain embodiments of the disclosure includemethods wherein biomarker RNA expression (transcription) is determined.Other embodiments of the disclosure include methods wherein proteinexpression in the biological sample is determined. See, e.g., Harlow etal., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory,Cold Spring Harbor, N.Y., (1988); Ausubel et al., Current Protocols inMolecular Biology, John Wiley & Sons, New York 3rd Edition, (1995);Kamel and Al-Amodi, Genomics Proteomics Bioinformatics 15:220-235(2017). For northern blot or RT-PCR analysis, RNA is isolated from thetumor tissue sample using RNAse free techniques. Such techniques arecommonly known in the art.

In one embodiment of the disclosure, a biological sample is obtainedfrom the patient and the biological sample is assayed for determinationof a biomarker, e.g., MDM2, expression or mutation status. In oneembodiment, flow cytometry is used to determine MDM2 expression.

In another embodiment of the disclosure, Northern blot analysis ofbiomarker transcription in a tumor cell sample is performed. Northernanalysis is a standard method for detection and/or quantitation of mRNAlevels in a sample. Initially, RNA is isolated from a sample to beassayed using Northern blot analysis. In the analysis, the RNA samplesare first separated by size via electrophoresis in an agarose gel underdenaturing conditions. The RNA is then transferred to a membrane,crosslinked and hybridized with a labeled probe. Typically, Northernhybridization involves polymerizing radiolabeled or nonisotopicallylabeled DNA, in vitro, or generation of oligonucleotides ashybridization probes. Typically, the membrane holding the RNA sample isprehybridized or blocked prior to probe hybridization to prevent theprobe from coating the membrane and, thus, to reduce non-specificbackground signal. After hybridization, typically, unhybridized probe isremoved by washing in several changes of buffer. Stringency of the washand hybridization conditions can be designed, selected and implementedby any practitioner of ordinary skill in the art. Detection isaccomplished using detectably labeled probes and a suitable detectionmethod. Radiolabeled and non-radiolabled probes and their use are wellknown in the art. The presence and or relative levels of expression ofthe biomarker being assayed can be quantified using, for example,densitometry.

In another embodiment, biomarker expression and/or mutation status isdetermined using RT-PCR. RT-PCR allows detection of the progress of aPCR amplification of a target gene in real time. Design of the primersand probes required to detect expression and/or mutation status of abiomarker of the disclosure is within the skill of a practitioner ofordinary skill in the art. RT-PCR can be used to determine the level ofRNA encoding a biomarker of the disclosure in a tumor tissue sample. Inan embodiment of the disclosure, RNA from the biological sample isisolated, under RNAse free conditions, than converted to DNA bytreatment with reverse transcriptase. Methods for reverse transcriptaseconversion of RNA to DNA are well known in the art. A description of PCRis provided in the following references: Mullis et al., Cold SpringHarbor Symp. Quant. Biol. 51:263 (1986); EP 50,424; EP 84,796; EP258,017; EP 237,362; EP 201,184; U.S. Pat. Nos. 4,683,202; 4,582,788;4,683,194.

RT-PCR probes depend on the 5′-3′ nuclease activity of the DNApolymerase used for PCR to hydrolyze an oligonucleotide that ishybridized to the target amplicon (biomarker gene). RT-PCR probes areoligonucleotides that have a fluorescent reporter dye attached to the 5′end and a quencher moiety coupled to the 3′ end (or vice versa). Theseprobes are designed to hybridize to an internal region of a PCR product.In the unhybridized state, the proximity of the fluor and the quenchmolecules prevents the detection of fluorescent signal from the probe.During PCR amplification, when the polymerase replicates a template onwhich an RT-PCR probe is bound, the 5′-3′ nuclease activity of thepolymerase cleaves the probe. This decouples the fluorescent andquenching dyes and FRET no longer occurs. Thus, fluorescence increasesin each cycle, in a manner proportional to the amount of probe cleavage.Fluorescence signal emitted from the reaction can be measured orfollowed over time using equipment which is commercially available usingroutine and conventional techniques.

In another embodiment of the disclosure, expression of proteins encodedby biomarkers are detected by western blot analysis. A western blot(also known as an immunoblot) is a method for protein detection in agiven sample of tissue homogenate or extract. It uses gelelectrophoresis to separate denatured proteins by mass. The proteins arethen transferred out of the gel and onto a membrane (e.g.,nitrocellulose or polyvinylidene fluoride (PVDF)), where they aredetected using a primary antibody that specifically bind to the protein.The bound antibody can then detected by a secondary antibody that isconjugated with a detectable label (e.g., biotin, horseradish peroxidaseor alkaline phosphatase). Detection of the secondary label signalindicates the presence of the protein.

In another embodiment of the disclosure, the expression of a proteinencoded by a biomarker is detected by enzyme-linked immunosorbent assay(ELISA). In one embodiment of the disclosure, “sandwich ELISA” comprisescoating a plate with a capture antibody; adding sample wherein anyantigen present binds to the capture antibody; adding a detectingantibody which also binds the antigen; adding an enzyme-linked secondaryantibody which binds to detecting antibody; and adding substrate whichis converted by an enzyme on the secondary antibody to a detectableform. Detection of the signal from the secondary antibody indicatespresence of the biomarker antigen protein.

In another embodiment of the disclosure, the expression of a biomarkeris evaluated by use of a gene chip or microarray. Such techniques arewithin ordinary skill held in the art.

The disclosure provides the following particular embodiments inconnection with biomarkers.

Embodiment I. A method of treating a subject having cancer, the methodcomprising:

(a) determining whether an overexpression of MDM2 is present or absentin a biological sample taken from the subject; and

(b) administering a therapeutically effective amount of a Compound ofthe Disclosure to the subject if an overexpression of MDM2 is present inthe biological sample.

Embodiment II. A method of identifying whether a subject having canceras a candidate for treatment with a Compound of the Disclosure, themethod comprising:

(a) determining whether an overexpression of MDM2 is present or absentin a biological sample taken from the subject; and

(b) identifying the subject as being a candidate for treatment if anoverexpression of MDM2 is present; or

(c) identifying the subject as not being a candidate for treatment if anoverexpression of MDM2 is absent.

Embodiment III. A method of predicting treatment outcome in a subjecthaving cancer, the method comprising determining whether anoverexpression of MDM2 is present or absent in a biological sample takenfrom the subject, wherein:

(a) the presence of an overexpression of MDM2 in the biological sampleindicates that administering a Compound of the Disclosure to the subjectwill produce a therapeutic response in the subject; and

(b) the absence of an overexpression of MDM2 in the biological sampleindicates that administering Compound of the Disclosure to the subjectwill not produce a therapeutic response in the subject.

Embodiment IV. A method, comprising administering a therapeuticallyeffective amount of Compound of the Disclosure to a subject in needthereof, wherein:

(a) the subject has cancer; and

(b) the cancer is characterized as having an overexpression of MDM2.

Embodiment V. The method of any one of Embodiments I-IV, wherein thecancer is any one of more of the cancers of Table 2.

Embodiment VI. The method of Embodiment V, wherein the cancer is ahematological cancer.

Embodiment VII. The method of Embodiment VI, wherein the hematologicalcancer is any one or more of the hematological cancers of Table 3.

Embodiment VIII. The method of Embodiment VII, wherein the hematologicalcancer is acute lymphocytic leukemia, chronic lymphocytic leukemia, oracute myeloid leukemia.

V. Definitions

The term “biological sample” as used herein refers any tissue or fluidfrom a patient that is suitable for detecting a biomarker, such as MDM2expression status. Examples of useful biological samples include, butare not limited to, biopsied tissues and/or cells, e.g., solid tumor,lymph gland, inflamed tissue, tissue and/or cells involved in acondition or disease, blood, plasma, serous fluid, cerebrospinal fluid,saliva, urine, lymph, cerebral spinal fluid, and the like. Othersuitable biological samples will be familiar to those of ordinary skillin the relevant arts. A biological sample can be analyzed for biomarkerexpression and/or mutation using any technique known in the art and canbe obtained using techniques that are well within the scope of ordinaryknowledge of a clinical practioner. In one embodiment of the disclosure,the biological sample comprises blood cells and/or bone marrow cells.

The term “a disease or condition wherein degradation of MDM2 proteinprovides a benefit” pertains to a disease or condition in which MDM2and/or an action of MDM2 is important or necessary, e.g., for the onset,progress, expression of that disease or condition, or a disease or acondition which is known to be treated by a MDM2 inhibitor or degrader.Examples of such conditions include, but are not limited to, a cancer, achronic autoimmune disease, an inflammatory disease, a proliferativedisease, sepsis, and a viral infection. One of ordinary skill in the artis readily able to determine whether a compound treats a disease orcondition mediated by MDM2 for any particular cell type, for example, byassays which conveniently can be used to assess the activity ofparticular compounds.

The term “second therapeutic agent” refers to a therapeutic agentdifferent from a Compound of the Disclosure and that is known to treatthe disease or condition of interest. For example when a cancer is thedisease or condition of interest, the second therapeutic agent can be aknown chemotherapeutic drug, like taxol, or radiation, for example.

The term “disease” or “condition” denotes disturbances and/or anomaliesthat as a rule are regarded as being pathological conditions orfunctions, and that can manifest themselves in the form of particularsigns, symptoms, and/or malfunctions. As demonstrated in the examplesbelow, a Compound of the Disclosure is a degrader of MDM2 protein andcan be used in treating diseases and conditions wherein degradation ofMDM2 provides a benefit.

As used herein, the terms “treat,” “treating,” “treatment,” refer toeliminating, reducing, or ameliorating a disease or condition, and/orsymptoms associated therewith. Although not precluded, treating adisease or condition does not require that the disease, condition, orsymptoms associated therewith be completely eliminated. As used herein,the terms “treat,” “treating,” “treatment,” may include “prophylactictreatment,” which refers to reducing the probability of redeveloping adisease or condition, or of a recurrence of a previously-controlleddisease or condition, in a subject who does not have, but is at risk ofor is susceptible to, redeveloping a disease or condition or arecurrence of the disease or condition. The term “treat” and synonymscontemplate administering a therapeutically effective amount of aCompound of the Disclosure to an individual in need of such treatment.

Within the meaning of the disclosure, “treatment” also includes relapseprophylaxis or phase prophylaxis, as well as the treatment of acute orchronic signs, symptoms and/or malfunctions. The treatment can beorientated symptomatically, for example, to suppress symptoms. It can beeffected over a short period, be oriented over a medium term, or can bea long-term treatment, for example within the context of a maintenancetherapy.

The term “therapeutically effective amount” or “effective dose” as usedherein refers to an amount of the active ingredient(s) that is(are)sufficient, when administered by a method of the disclosure, toefficaciously deliver the active ingredient(s) for the treatment ofcondition or disease of interest to an individual in need thereof. Inthe case of a cancer or other proliferation disorder, thetherapeutically effective amount of the agent may reduce (i.e., retardto some extent and preferably stop) unwanted cellular proliferation;reduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,retard to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., retard to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; reduceMDM2 signaling in the target cells; and/or relieve, to some extent, oneor more of the symptoms associated with the cancer. To the extent theadministered compound or composition prevents growth and/or killsexisting cancer cells, it may be cytostatic and/or cytotoxic.

In one embodiment, with respect to the treatment of cancer, atherapeutically effective amount refers to the amount of a Compound ofDisclosure that (a) decreases the (1) rate of tumor growth; (2) tumormass; (3) buildup of abnormal cells in tissues and organs; or (4) thenumber of metastases, in a subject by 5% or more, e.g., 10% or more, 15%or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% ormore, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more,70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95%or more; or (b) increases (1) the time to tumor progression; (2) tumorcell apoptosis; or (3) survival time, in a subject by 5% or more, e.g.,10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% ormore, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more,65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% ormore, or 95% or more.

Likewise, the term “therapeutic response in a subject” refers to (a) adecrease in the (1) rate of tumor growth; (2) tumor mass; (3) buildup ofabnormal cells in tissues and organs; or (4) the number of metastases,in that subject by 5% or more, e.g., 10% or more, 15% or more, 20% ormore, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more,50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% ormore, 80% or more, 85% or more, 90% or more, or 95% or more; or (b) anincrease in (1) the time to tumor progression; (2) tumor cell apoptosis;or (3) survival time, in that subject by 5% or more, e.g., 10% or more,15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% ormore, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more,70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95%or more.

The term “container” means any receptacle and closure therefore suitablefor storing, shipping, dispensing, and/or handling a pharmaceuticalproduct.

The term “insert” means information accompanying a pharmaceuticalproduct that provides a description of how to administer the product,along with the safety and efficacy data required to allow the physician,pharmacist, and patient to make an informed decision regarding use ofthe product. The package insert generally is regarded as the “label” fora pharmaceutical product.

“Concurrent administration,” “administered in combination,”“simultaneous administration,” and similar phrases mean that two or moreagents are administered concurrently to the subject being treated. By“concurrently,” it is meant that each agent is administered eithersimultaneously or sequentially in any order at different points in time.However, if not administered simultaneously, it is meant that they areadministered to an individual in a sequence and sufficiently close intime so as to provide the desired therapeutic effect and can act inconcert. For example, a Compound of the Disclosure can be administeredat the same time or sequentially in any order at different points intime as a second therapeutic agent. A Compound of the Disclosure and thesecond therapeutic agent can be administered separately, in anyappropriate form and by any suitable route. When a Compound of theDisclosure and the second therapeutic agent are not administeredconcurrently, it is understood that they can be administered in anyorder to a subject in need thereof. For example, a Compound of theDisclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, orsubsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks,or 12 weeks after) the administration of a second therapeutic agenttreatment modality (e.g., radiotherapy), to an individual in needthereof. In various embodiments, a Compound of the Disclosure and thesecond therapeutic agent are administered 1 minute apart, 10 minutesapart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hoursapart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, nomore than 24 hours apart or no more than 48 hours apart. In oneembodiment, the components of the combination therapies are administeredat about 1 minute to about 24 hours apart.

The use of the terms “a”, “an”, “the”, and similar referents in thecontext of describing the disclosure (especially in the context of theclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated. Recitation of ranges of values herein merelyare intended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended to better illustrate the disclosure and is not a limitation onthe scope of the disclosure unless otherwise claimed. No language in thespecification should be construed as indicating any non-claimed elementas essential to the practice of the disclosure.

The term “about,” as used herein, includes the recited number±10%. Thus,“about 10” means 9 to 11.

The present disclosure encompasses any of the Compounds of theDisclosure being isotopically-labeled, i.e., radiolabeled, by having oneor more atoms replaced by an atom having a different atomic mass or massnumber. Examples of isotopes that can be incorporated into Compounds ofthe Disclosure include isotopes of hydrogen, carbon, nitrogen, sulfur,oxygen, fluorine, and chlorine, such as ²H (or deuterium (D)), ³H, ¹¹C,³C ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, and ³⁶Cl, e.g., ²H, ³H, and ¹³C. In oneembodiment, a portion of the atoms at a position within a Compound ofthe Disclosure are replaced, i.e., the Compound of the Disclosure isenriched at a position with an atom having a different atomic mass ormass number. In one embodiment, at least about 1% of the atoms arereplaced with atoms having a different atomic mass or mass number. Inanother embodiment, at least about 5%, at least about 10%, at leastabout 15%, at least about 20%, at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, at leastabout 50%, at least about 55%, at least about 60%, at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 95%, or at least about100% of the atoms are replaced with atoms having a different atomic massor mass number.

Compounds of the Disclosure have asymmetric centers and may thus giverise to enantiomers, diastereomers, and other stereoisomeric forms. Thepresent disclosure encompasses the use of all such possible forms, aswell as their racemic and resolved forms and mixtures thereof. Theindividual enantiomers can be separated according to methods known inthe art in view of the present disclosure. When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that theyinclude both E and Z geometric isomers. All tautomers are alsoencompassed by the present disclosure.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” or “asymmetric carbon atom” refers to a carbonatom to which four different groups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive. In one embodiment, Compounds of theDisclosure are racemic.

The term “absolute configuration” refers to the spatial arrangement ofthe atoms of a chiral molecular entity (or group) and its stereochemicaldescription, e.g., R or S.

The stereochemical terms and conventions used in the specification aremeant to be consistent with those described in Pure & Appl. Chem 68:2193(1996), unless otherwise indicated.

The term “enantiomeric excess” or “ee” refers to a measure for how muchof one enantiomer is present compared to the other. For a mixture of Rand S enantiomers, the percent enantiomeric excess is defined as|R−S|*100, where R and S are the respective mole or weight fractions ofenantiomers in a mixture such that R+S=1. With knowledge of the opticalrotation of a chiral substance, the percent enantiomeric excess isdefined as ([α]_(obs)/[α]_(max))*100, where [α]_(obs) is the opticalrotation of the mixture of enantiomers and [α]_(max) is the opticalrotation of the pure enantiomer. Determination of enantiomeric excess ispossible using a variety of analytical techniques, including NMRspectroscopy, chiral column chromatography or optical polarimetry.

The term “diastereomeric excess” or “de” refers to a measure for howmuch of one diastereomer is present compared to another, and is definedby analogy to enantiomeric excess. Determination of diastereomericexcess is possible using a variety of analytical techniques, includingNMR spectroscopy and column chromatography.

General Synthesis of Compounds

Compounds of the Disclosure are prepared using methods known to thoseskilled in the art in view of this disclosure, or by the illustrativemethods shown in the General Schemes below. Suitable protecting can beemployed in the synthesis, if needed. See Wuts, P. G. M.; Greene, T. W.,“Greene's Protective Groups in Organic Synthesis”, 5th Ed., J. Wiley &Sons, N Y, 2014.

In General Scheme 1, compound A is reacted with a compound of Formula Bin an organic solvent to give a compound of Formula I. Suitableamine-to-amide coupling reagents and conditions, e.g., HATU/base,HBTU/base, or EDCI/HOBt/base, are well known in the art. See Montalbettiand Falque, Tetrahedron 61:10827-10852 (2005).

In General Scheme 2, a compound of Formula C is reacted with compound ofFormula D in an organic solvent to give a compound of Formula I.

In one embodiment, the disclosure provides a compound of Formula D,wherein X, Y, L, Z, and A are as defined in connection with Formula I assynthetic intermediates that are useful to prepare Compounds of theDisclosure.

In another embodiment, the disclosure provides:

(3-(4-((1-((1r,4r)-4-aminocyclohexane-1-carbonyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione)as a synthetic intermediate used to prepare Compounds of the Disclosure.

EXAMPLES Example 1 Synthesis of(3′R,4'S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-N-((1r,4R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carbonyl)cyclohexyl)-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamide(Cpd. No. 4)

To a solution of Intermediate 1 (19 g, 1.0 equiv) and methyl4-aminocyclohexane-1-carboxylate (1.1 equiv) in DCM (500 mL), was addedDIPEA (1.2 equiv) and HATU (1.2 equiv). Then the mixture was stirred atr.t. for 2 h. The mixture was quenched with aq. NaHCO₃ and extractedwith ethyl acetate three times. The organic layer was washed with brine,dried with Na₂SO₄, filtered, and concentrated to give the crude productwhich was purified by column chromatography to produce pure Intermediate2 (82% yield, purity >95%). MS(ESI) m/z (M+H)⁺=602.36; calcd: 602.53;R_(t)=4.98 min; ¹H NMR (400 MHz, methanol-d4) δ 7.62 (ddd, J=8.0, 6.3,1.6 Hz, 1H), 7.40 (dd, J=8.2, 2.5 Hz, 1H), 7.21 (ddd, J=8.4, 7.0, 1.6Hz, 1H), 7.06-6.99 (m, 2H), 6.72 (d, J=1.9 Hz, 1H), 4.66 (d, J=9.4 Hz,1H), 4.50 (d, J=9.4 Hz, 1H), 3.66 (s, 3H), 3.66-3.52 (m, 4H), 2.34 (tt,J=12.1, 3.5 Hz, 1H), 2.09-1.77 (m, 6H), 1.77-1.43 (m, 8H), 1.43-1.24 (m,2H), 1.14-0.99 (m, 1H), 0.94 (td, J=13.2, 4.5 Hz, 1H).

To a solution of Intermediate 3 (30 g), and amine 4 (HCl salt) (1 equiv)in DMF (450 mL) was added DIPEA (2 equiv). After stirring for 5-10minute at r.t., HATU (1.1 eq) was added. Then the mixture was stirredfor 30 mins. The reaction was quenched with H₂O (1100 mL). The resultingprecipitate was filtered, washed with water to give the crude product(purity=93-94%). The solid was further purified by prep-HPLC to giveCpd. No. 4 as a TFA salt. MS(ESI) m/z (M+H)⁺=921.56; calcd: 921.89;R_(t)=5.09 min; ¹H NMR (400 MHz, methanol-d4) δ 8.22 (d, J=7.7 Hz, 1H),7.76 (dd, J=7.6, 1.1 Hz, 1H), 7.69-7.58 (m, 2H), 7.54-7.46 (m, 2H), 7.39(ddd, J=8.6, 7.2, 1.5 Hz, 1H), 7.17 (td, J=8.0, 1.1 Hz, 1H), 7.10 (dd,J=8.2, 2.0 Hz, 1H), 6.79 (d, J=1.9 Hz, 1H), 5.17 (dd, J=13.3, 5.2 Hz,1H), 5.10 (d, J=11.1 Hz, 1H), 4.79 (d, J=11.2 Hz, 1H), 4.56-4.41 (m,2H), 4.03-3.90 (m, 1H), 3.87-3.75 (m, 1H), 3.74-3.57 (m, 1H), 3.46-3.35(m, 1H), 3.06-2.73 (m, 5H), 2.62-2.44 (m, 2H), 2.25-2.11 (m, 2H),2.04-1.85 (m, 6H), 1.82-1.44 (m, 10H), 1.33-1.16 (m, 3H), 1.03-0.87 (m,1H).

Example 2 Synthesis of3-(1-oxo-4-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione(Intermediate 4)

To the mixture of the Intermediate 6 (50 g, 155 mmol),1-Boc-4-ethynylpiperidine 5 (43 g), Pd(PPh₃)₂Cl₂ (8.7 g, 12.4 mmol), andCuI (4.72 g, 24.8 mmol), 750 mL of DMF and 750 mL of TEA were added. Thesolution was purged and refilled with Ar three times under sonication.The solution was stirred at 80° C. overnight. Then to the reaction wasadded water and extracted with ethyl acetate. The combined ethyl acetate(about 5) layers were washed with brine three times. Then the resultingprecipitate was filtered, washed with hexane to give Intermediate 7. Forfurther purification, methanol was added to the product and the mixturewas stirred for 10 min. Then the precipitate was filtered, and washedwith hexane to give the pure Intermediate 7 (70-80% yield, purity >95%).

3-(1-oxo-4-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione(Intermediate 4): The above obtained Intermediate 7 (30 g) was suspendedin HCl in dioxane (150 mL). The solution was stirred at room temperaturefor 30 min. Then the resulting precipitate was filtered, washed withhexane to give the pure Intermediate 4 (90% yield, purity >95%). MS(ESI)m/z (M+H)⁺=352.31; calcd: 351.41; R_(t)=1.04 min; ¹H NMR (400 MHz,methanol-d4) δ 7.79 (dd, J=7.6, 1.0 Hz, 1H), 7.67 (dd, J=7.7, 1.0 Hz,1H), 7.53 (t, J=7.7 Hz, 1H), 5.19 (dd, J=13.3, 5.1 Hz, 1H), 4.59-4.41(m, 2H), 3.47-3.36 (m, 2H), 3.24-3.09 (m, 3H), 3.00-2.85 (m, 1H),2.84-2.73 (m, 1H), 2.53 (qd, J=13.2, 4.6 Hz, 1H), 2.26-2.13 (m, 3H),2.04-1.90 (m, 2H).

Example 3 Synthesis of tert-butyl 4-ethynylpiperidine-1-carboxylate(Intermediate 5)

K₂CO₃ (260 g) was added to a solution of N-Boc-piperidine-4-aldehyde(100 g) in MeOH (500 mL) at 0° C. Then dimethyl1-diazoacetonylphosphonate (108 g) was slowly added at 0° C. Afterstirring at room temperature for 4 h, the mixture was quenched withwater, then most of the MeOH was removed by rotary evaporation. Theresidue was extracted with ethyl acetate, and the organic layer washedwith brine, dried with Na₂SO₄, and concentrated to give Intermediate 5which was used in next step without further purification.

Example 4 Synthesis of3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate 6)

To a solution of Intermediate 10 (150 g) in MeOH (1500 mL) was addedconc. H₂SO₄ (80 mL) dropwise. The reaction mixture was stirred overnightat reflux. After cooling to room temperature, the MeOH was removed byrotary evaporation. Then water was added, and the mixture was extractedwith Et₂O three times. The organic layer was washed with brine, driedwith Na₂SO₄, filtered and concentrated to give the crude productIntermediate 11 which was used in next step without furtherpurification.

To a solution of Intermediate 11 (160 g) in benzene (1300 mL) was addedN-bromosuccinamide (149 g) and benzoyl peroxide (16 g). The reactionmixture was stirred overnight at reflux. After cooling to roomtemperature, aqueous Na₂S203 was added and the mixture was stirred for10-20 min at room temperature. The mixture was extracted with benzenetwo times. The organic layer was washed with brine, dried with Na₂SO₄,filtered and concentrated to give the crude product. Then ethyl acetatewas added and the mixture was stirred for several minutes. The resultingprecipitate was filtered, and the filtrate was concentrated to give theproduct Intermediate 12 which was used in the next step without furtherpurification.

To a solution of Intermediate 12 (183 g) in CH₃CN (1000 mL) was added3-aminopiperidine-2,6-dione (1.2 eq) and triethylamine (80 g) and thereaction mixture was stirred at 80° C. After complete consumption ofIntermediate 12 as detected by TLC, the mixture was cooled to roomtemperature then ethyl acetate (1000 mL) and water (1000 mL) were added.The mixture was stirred for 10-20 min, and the resulting precipitate wasfiltered, and washed with hexane. The solid was then dried in adesiccator under vacuum (overnight) to produce Intermediate 6 (142 g) asa solid, which was used in next step without further purification.

Example 5

The following Compounds of the Disclosure were prepare using theprocedures described in Examples 1-4 and WO 2017/176957, and methodsknown in the art.

Cpd No. 1: LC-MS(ESI) m/z (M+H)⁺=996.00; calcd: 996.02; R_(t)=4.00 min.

Cpd. No. 2: LC-MS(ESI) m/z (M+H)⁺=921.46; calcd: 921.89; R_(t)=5.16 min.

Cpd. No. 3: LC-MS(ESI) m/z (M+H)⁺=897.53; calcd: 897.87; R_(t)=4.98 min;¹H NMR (400 MHz, methanol-d4) δ 7.74 (dd, J=7.7, 1.1 Hz, 1H), 7.63-7.54(m, 3H), 7.49 (t, J=7.6 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.21-7.12 (m,2H), 6.80 (d, J=1.8 Hz, 1H), 5.24-5.11 (m, 2H), 4.62-4.42 (m, 4H),3.69-3.55 (m, 1H), 3.01-2.85 (m, 2H), 2.85-2.74 (m, 1H), 2.67-2.54 (m,1H), 2.51 (t, J=6.8 Hz, 2H), 2.24-2.13 (m, 1H), 2.10-1.98 (m, 1H),1.98-1.67 (m, 7H), 1.64-1.40 (m, 4H), 1.25-1.10 (m, 2H), 0.88 (s, 9H).

Cpd. No. 5: LC-MS(ESI) m/z (M+H)⁺=936.54; calcd: 936.91; R_(t)=4.06 min.

Cpd. No. 6: LC-MS(ESI) m/z (M+H)⁺=947.54; calcd: 947.93; R_(t)=5.44 min;¹H NMR (400 MHz, methanol-d4) δ 7.76 (dd, J=7.6, 1.1 Hz, 1H), 7.71-7.58(m, 3H), 7.55-7.44 (m, 2H), 7.40 (ddd, J=8.6, 7.3, 1.6 Hz, 1H), 7.16(td, J=8.0, 1.2 Hz, 1H), 7.10 (dd, J=8.2, 2.0 Hz, 1H), 6.78 (d, J=2.0Hz, 1H), 5.17 (dd, J=13.3, 5.2 Hz, 1H), 5.11 (d, J=11.2 Hz, 1H), 4.72(d, J=11.2 Hz, 1H), 4.55-4.40 (m, 2H), 4.06-3.91 (m, 2H), 3.40 (t,J=10.3 Hz, 2H), 3.05-2.85 (m, 2H), 2.85-2.72 (m, 2H), 2.53 (qd, J=13.3,4.7 Hz, 1H), 2.25-2.12 (m, 2H), 2.02-1.71 (m, 19H), 1.71-1.59 (m, 2H),1.59-1.44 (m, 1H), 1.31-1.13 (m, 2H).

Cpd. No. 7: LC-MS(ESI) m/z (M+H)⁺=922.52; calcd: 922.88; R_(t)=4.24 min.

Cpd. No. 8: LC-MS(ESI) m/z (M+H)⁺=938.54; calcd: 938.92; R_(t)=4.38 min.

Cpd. No. 9: LC-MS(ESI) m/z (M+H)⁺=935.52; calcd: 935.92; R_(t)=5.47 min.

Cpd. No. 10: LC-MS(ESI) m/z (M+H)⁺=961.54; calcd: 961.96; R_(t)=5.92min.

Cpd. No. 11: LC-MS(ESI) m/z (M+H)⁺=905.50; calcd: 905.85; R_(t)=5.07min; ¹H NMR (400 MHz, methanol-d4) δ 7.76 (dd, J=7.7, 1.0 Hz, 1H),7.66-7.58 (m, 2H), 7.54-7.46 (m, 2H), 7.39 (ddd, J=8.5, 7.3, 1.5 Hz,1H), 7.16 (td, J=8.1, 1.2 Hz, 1H), 7.11 (dd, J=8.2, 2.0 Hz, 1H), 6.78(d, J=1.9 Hz, 1H), 5.17 (dd, J=13.3, 5.2 Hz, 1H), 5.00 (d, J=11.0 Hz,1H), 4.79 (d, J=11.0 Hz, 1H), 4.58-4.41 (m, 2H), 4.00-3.84 (m, 2H),3.55-3.44 (m, 1H), 3.42-3.33 (m, 1H), 3.08-2.96 (m, 1H), 2.97-2.86 (m,1H), 2.86-2.73 (m, 2H), 2.53 (qd, J=13.2, 4.7 Hz, 1H), 2.37 (s, 6H),2.24-2.08 (m, 2H), 2.03-1.81 (m, 5H), 1.81-1.60 (m, 4H), 1.58-1.42 (m,1H), 1.29-1.13 (m, 2H).

Cpd. No. 12: LC-MS(ESI) m/z (M+H)⁺=893.48; calcd: 893.84; R_(t)=4.85min; ¹H NMR (400 MHz, methanol-d4) δ 7.76 (dd, J=7.6, 1.1 Hz, 1H),7.69-7.60 (m, 2H), 7.55-7.46 (m, 2H), 7.40 (ddd, J=8.5, 7.2, 1.5 Hz,1H), 7.19 (td, J=8.1, 1.2 Hz, 1H), 7.10 (dd, J=8.2, 2.0 Hz, 1H), 6.79(d, J=1.9 Hz, 1H), 5.18 (dd, J=13.3, 5.2 Hz, 1H), 5.07 (d, J=11.0 Hz,1H), 4.80 (dd, J=11.1, 2.1 Hz, 1H), 4.57-4.41 (m, 2H), 4.30 (p, J=7.6Hz, 1H), 4.04-3.87 (m, 1H), 3.61-3.50 (m, 1H), 3.46-3.35 (m, 1H),3.29-3.15 (m, 2H), 3.05-2.85 (m, 2H), 2.85-2.73 (m, 2H), 2.65-2.40 (m,3H), 2.24-2.11 (m, 3H), 2.06-1.80 (m, 6H), 1.76 (d, J=12.6 Hz, 2H),1.73-1.58 (m, 2H), 1.51 (q, J=13.8 Hz, 1H), 1.27-1.13 (m, 2H).

Cpd. No. 13: LC-MS(ESI) m/z (M+H)⁺=945.55; calcd: 975.98; R_(t)=6.01min; ¹H NMR (400 MHz, methanol-d4) δ 7.76 (dd, J=7.7, 1.1 Hz, 1H), 7.70(s, 1H), 7.67-7.60 (m, 2H), 7.55-7.46 (m, 2H), 7.40 (ddd, J=8.5, 7.2,1.5 Hz, 1H), 7.16 (td, J=8.1, 1.2 Hz, 1H), 7.11 (dd, J=8.3, 2.0 Hz, 1H),6.80 (d, J=1.9 Hz, 1H), 5.17 (dd, J=13.3, 5.2 Hz, 1H), 5.09 (d, J=11.1Hz, 1H), 4.72 (d, J=11.1 Hz, 1H), 4.56-4.40 (m, 2H), 4.06-3.92 (m, 2H),3.40 (t, J=10.8 Hz, 2H), 3.06-2.84 (m, 2H), 2.84-2.73 (m, 1H), 2.68 (d,J=14.1 Hz, 1H), 2.53 (qd, J=13.2, 4.7 Hz, 1H), 2.24-2.12 (m, 1H),2.13-2.00 (m, 2H), 2.00-1.87 (m, 8H), 1.85 (d, J=3.4 Hz, 1H), 1.84-1.72(m, 6H), 1.71-1.56 (m, 3H), 1.50-1.28 (m, 3H), 1.01 (s, 3H), 0.76 (s,3H).

Cpd. No. 14: LC-MS(ESI) m/z (M+H)⁺=931.58; calcd: 931.48; R_(t)=5.27min; ¹H NMR (400 MHz, methanol-d4) δ 7.76 (dd, J=7.7, 1.1 Hz, 1H), 7.68(s, 1H), 7.62 (dd, J=7.7, 1.1 Hz, 1H), 7.55-7.44 (m, 3H), 7.25-7.11 (m,2H), 7.10 (dd, J=8.2, 2.0 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H), 5.17 (dd,J=13.3, 5.2 Hz, 1H), 5.11 (d, J=11.2 Hz, 1H), 4.70 (d, J=11.2 Hz, 1H),4.56-4.41 (m, 2H), 4.05-3.91 (m, 2H), 3.40 (t, J=11.1 Hz, 2H), 3.05-2.85(m, 2H), 2.85-2.74 (m, 2H), 2.53 (qd, J=13.2, 4.7 Hz, 1H), 2.23-2.13 (m,2H), 2.02-1.84 (m, 11H), 1.86-1.71 (m, 8H), 1.72-1.58 (m, 2H), 1.52 (q,J=13.7 Hz, 1H), 1.30-1.13 (m, 2H).

Cpd. No. 15: LC-MS(ESI) m/z (M+H)⁺=935.52; calcd: 935.92; R_(t)=4.81min.

Cpd. No. 16: LC-MS(ESI) m/z (M+H)⁺=949.54; calcd: 949.95; R_(t)=4.86min.

Cpd. No. 17: LC-MS(ESI) m/z (M+H)⁺=905.54; calcd: 905.44; R_(t)=4.83min; ¹H NMR (400 MHz, methanol-d4) δ 8.18 (d, J=7.8 Hz, 1H), 7.76 (dd,J=7.7, 1.1 Hz, 1H), 7.62 (dd, J=7.7, 1.1 Hz, 1H), 7.55-7.45 (m, 3H),7.24-7.11 (m, 3H), 7.10 (dd, J=8.2, 2.0 Hz, 1H), 6.78 (d, J=1.9 Hz, 1H),5.16 (dd, J=13.3, 5.2 Hz, 1H), 5.12 (d, J=11.1 Hz, 1H), 4.78 (d, J=11.2Hz, 1H), 4.56-4.40 (m, 2H), 4.02-3.90 (m, 1H), 3.86-3.75 (m, 1H),3.73-3.59 (m, 1H), 3.46-3.34 (m, 2H), 3.05-2.82 (m, 3H), 2.84-2.73 (m,1H), 2.63-2.44 (m, 2H), 2.25-2.12 (m, 2H), 2.05-1.83 (m, 7H), 1.83-1.43(m, 11H), 1.34-1.16 (m, 3H), 1.03-0.88 (m, 1H).

Cpd. No. 22: LC-MS(ESI) m/z (M+H)⁺=935.48; calcd: 935.92; R_(t)=4.73min.

Cpd. No. 23: LC-MS(ESI) m/z (M+H)⁺=907.48; calcd: 907.87; R_(t)=4.60min.

Cpd. No. 24: LC-MS(ESI) m/z (M+H)⁺=943.47; calcd: 943.90; R_(t)=6.42min.

Cpd. No. 25: LC-MS(ESI) m/z (M+H)⁺=861.56; calcd: 861.41; R_(t)=4.36min.

Cpd. No. 26: LC-MS(ESI) m/z (M+H)⁺=877.53; calcd: 877.86; R_(t)=4.60min.

Cpd. No. 27: LC-MS(ESI) m/z (M+H)⁺=843.55; calcd: 843.42; R_(t)=4.18min.

Cpd. No. 28: LC-MS(ESI) m/z (M+H)⁺=945.48; calcd: 945.87; R_(t)=6.24min.

Cpd. No. 29: LC-MS(ESI) m/z (M+H)⁺=921.57; calcd: 921.89; R_(t)=4.70min.

Cpd. No. 30: LC-MS(ESI) m/z (M+H)⁺=935.56; calcd: 935.92; R_(t)=5.27min.

Cpd. No. 31: LC-MS(ESI) m/z (M+H)⁺=961.59; calcd: 961.96; R_(t)=5.81min.

Cpd. No. 32: LC-MS(ESI) m/z (M+H)⁺=893.53; calcd: 893.84; R_(t)=4.62min.

Cpd. No. 33: LC-MS(ESI) m/z (M+H)⁺=919.54; calcd: 919.88; R_(t)=4.93min.

Cpd. No. 34: LC-MS(ESI) m/z (M+H)⁺=1178.07; calcd: 1178.30; R_(t)=6.72min.

Cpd. No. 35: LC-MS(ESI) m/z (M+2H)⁺=629.12; calcd: 629.16; R_(t)=5.63min.

Cpd. No. 36: LC-MS(ESI) m/z (M+2H)⁺=635.46; calcd: 635.66; R_(t)=5.05min.

Cpd. No. 37: LC-MS(ESI) m/z (M+H)⁺=875.45; calcd: 875.90; R_(t)=6.11min.

Cpd. No. 38 LC-MS(ESI) m/z (M+H)⁺=951.52; calcd: 951.94; R_(t)=7.33 min;¹H NMR (400 MHz, methanol-d4) δ 7.90 (s, 1H), 7.76 (dd, J=7.6, 1.0 Hz,1H), 7.67-7.60 (m, 2H), 7.51 (t, J=7.6 Hz, 1H), 7.41-7.35 (m, 2H), 7.32(t, J=8.4 Hz, 1H), 7.27-7.16 (m, 2H), 5.17 (dd, J=13.3, 5.2 Hz, 1H),4.70 (d, J=7.8 Hz, 1H), 4.57-4.42 (m, 2H), 4.31 (d, J=7.7 Hz, 1H),4.10-3.99 (m, 2H), 3.94 (d, J=9.3 Hz, 1H), 3.48-3.38 (m, 2H), 3.07-2.97(m, 1H), 2.98-2.84 (m, 2H), 2.84-2.72 (m, 2H), 2.54 (qd, J=13.3, 4.7 Hz,2H), 2.19 (ddq, J=10.4, 5.3, 2.6 Hz, 1H), 2.06-1.91 (m, 10H), 1.75-1.57(m, 3H), 1.35-1.26 (m, 2H), 0.93 (s, 9H).

Example 6 Cell Growth Inhibition

The effect of representative Compounds of the Disclosure on cellviability was determined in a 4-day proliferation assay. See Tables 4.Cells were maintained in the appropriate culture medium with 10% FBS at37° C. and an atmosphere of 5% CO₂. Also, the effect of a MDM2 inhibitor(Cpd. A; see Compound Example No. 22 of U.S. Pat. No. 8,629,141) and aknown MDM2 degrader (Cpd. D, see Cpd. No. 175 of WO 2017/0176957) oncell viability in various cell lines is also included in Table 5. Cpd.Nos. 4 and 6 of the instant disclosure are surprisingly more potent inall cell lines tested as compared to Cpds. A and D. The structure ofCpd. A is:

The structure of Cpd. D is:

Cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, N.Y.,cat #3595) at a density of 2,000-3,000 cells/well in 100 μL of culturemedium. Compounds were serially diluted in the appropriate medium, and100 μL of the diluted compounds were added to the appropriate wells ofthe cell plate. After the addition of compounds, the cells wereincubated at 37° C. in an atmosphere of 5% CO₂ for 4 days. Cellviability was determined using the WST(2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium,monosodium salt) Cell Counting-8 Kit (Dojindo Molecular Technologies,Inc., Rockville, Md.) according to the manufacturers' instructions.

WST-8 reagent was added to each well at a final concentration of 10%(v/v), and then the plates were incubated at 37° C. for 1-2 hours forcolor development. The absorbance was measured at 450 nm using aSPECTRAmax PLUS plate reader (Molecular Devices, Sunnyvale, Calif.). Thereadings were normalized to the DMSO-treated cells and the half maximalinhibitory concentration (IC₅₀) was calculated by nonlinear regression(four parameters sigmoid fitted with variable slope, least squares fit,and no constraint) analysis using the GraphPad Prism 5 software(GraphPad Software, La Jolla, Calif.).

TABLE 4 Cpd. RS4; 11 Cells IC₅₀ No. (nM) 1 2.4 2 4.7 3 0.62 5 3.1 7 >1008 4.5 9 2.8 10 8.0 11 0.3 12 1.4 13 6 14 11 15 60 16 >100 22 >10023 >100 24 6.6 25 >100 26 0.7 27 >100 28 >100 29 >100 30 1.2 31 2.9 321.3 33 1.2 37 >100 38 56

TABLE 5 IC₅₀ (μM) Cpd. Cpd. Cpd. Cpd. Cell line Cell Type A D No. 4 No.6 RS4; 11 Precursor cell 0.138 0.0029 0.00072 0.0024 lymphoblasticleukemia MV-4; Acute 0.01 0.0023 0.0064 11 biphenotypic B myelomonocyticleukemia OCI- Acute myeloid 0.11 0.021 0.069 AML-2 leukemia OCI- Acutemyeloid 0.15 0.023 0.071 AML-5 leukemia MOLM- Acute myeloid 0.034 0.00510.018 13 leukemia MOLM- Acute myeloid 0.078 0.0078 0.025 14 leukemiaML-2 Acute myeloid 0.011 0.0012 0.0049 leukemia SIG-M5 Acute myeloid0.11 0.021 0.063 leukemia LNCaP Prostate 0.033 0.0032 0.013 carcinoma22RV1 Prostate 1.327 0.045 0.014 0.042 carcinoma HCT116 Colorectal 0.40.086 0.31 carcinoma

Example 7 In Vivo Efficacy Studies in the LNCaP and 22Rv1 Human ProstateXenograft Models

LNCaP (human prostate) tumor cells were harvested with Trypsin(0.25%)-EDTA (0.53 mM) (GIBCO™, Invitrogen Corp.), growth medium addedand cells placed on ice. A cell sample was mixed 1:1 with Trypan Blue(GIBCO™ Invitrogen Corp.) and counted on a hemocytometer to determinethe number of live/dead cells. Cells were washed twice with 1×PBS(GIBCO™, Invitrogen Corp.) and resuspended in an ice cold mixture of 1:1PBS and Matrigel (BD Biosciences, Invitrogen Corp.) for a final Matrigelprotein concentration of 5 mg/ml. LNCaP tumors were inoculated into maleC.B-17 SCID mice at 5×10⁶ cells in 0.1 ml with Matrigel. Cells wereinjected s.c. into the flank region of each mouse. The size of tumorsgrowing in the mice was measured in two dimensions using calipers. Tumorvolume (mm³)=(A×B²)/2 where A and B are the tumor length and width (inmm), respectively. During treatment, tumor volume and body weight wasmeasured two or three times a week. After the treatment was stopped,tumor volume and body weight was measured at least once a week. Beforetreatment began, tumors were allowed to grow to 100-200 mm³ in volume.Mice with tumors within acceptable size range were randomized intotreatment groups of 7 mice per group. Experimental compounds were givenintravenously, in a solution of 25% PEG 400: 9% Cremophor EL: 66% PBS),once per week for 5 weeks. Using similar protocols, the antitumoractivity of Cpd. No. 4 and Cpd. No. 6 was evaluated in the 22Rv1 humanprostate cancer model in mice. See FIG. 1 and FIG. 2.

Example 8 In Vivo Efficacy Studies in the RS4;11 Human ALL XenograftModel

RS4;11 tumors were grown in suspension. A cell sample was mixed 1:1 withTrypan Blue (GIBCO™, Invitrogen Corp.) and counted on a hemocytometer todetermine the number of live/dead cells. Cells were washed twice with1×PBS (GIBCO™, Invitrogen Corp.) and resuspended in an ice cold mixtureof 1:1 PBS and Matrigel (BD Biosciences, Invitrogen Corp.) for a finalMatrigel protein concentration of 5 mg/mL. RS4;11 tumors were inoculatedinto female C.B-17 SCID mice at 5×10⁶ cells in 0.1 mL with Matrigel.Cells were injected s.c. into the flank region of each mouse. The sizeof tumors growing in the mice was measured in two dimensions usingcalipers. Tumor volume (mm³)=(A×B²)/2 where A and B are the tumor lengthand width (in mm), respectively. During treatment, tumor volume and bodyweight was measured two or three times a week. After the treatment wasstopped, tumor volume and body weight was measured at least once a week.Before treatment began, tumors were allowed to grow to 60-140 mm³ involume. Mice with tumors within acceptable size range were randomizedinto treatment groups of 5 mice per group. Cpd. No. 4 and Cpd. No. 6were given intravenously, in a solution of 25% PEG 400: 9% Cremophor EL:66% PBS, three times per week for 2 weeks and orally in a solution ofPEG 200, 5 times per week for 2 weeks. See FIG. 3.

Example 9 Survival Studies Conditioning

Female NOD SCID (NOD.CB17-Prkdc^(scid)/NCrHsd) mice were obtained fromEnvigo, USA. At 8-10 weeks old, the mice were pretreated with 150 mg/kgcyclophosphamide (CPM) (NDC 10019-956-01 Baxter Healthcare Corporation,Deerfield, Ill.) obtained from the UM Hospital Pharmacy and dissolved toa concentration of 15 mg/mL with sterile saline (0.9% sodium chlorideNDC 0409-4888-06). The mice were injected IP, with a volume of 10 ul/gbody weight, on two days 24 hours apart. At the start of conditioning,diet gel was provided in each cage to mitigate the effects of treatmentand subsequently supplied throughout the experiment.

Cell Inoculation

On the following day, 24 hours after the second dose of CPM, each animalwas injected with 5×10⁶ RS4;11 cells in 0.15 mL via the lateral tailvein. RS4;11 cells were obtained from ATCC (certified free of mouse andhuman virus), grown in RPMI medium supplemented withpenicillin/streptomycin (Lifetech) and 10% fetal bovine serum (Sigma) ina 5% CO₂ incubator. For injection, cells were washed twice in PBS andre-suspended in sterile saline at a concentration of 3.3×10⁷ RS4;11cells per mL.

Treatment

Thirteen days after cell injection, mice were randomized into treatmentgroups of 9-10 mice and allowed to acclimate to their cage mates. Thefollowing day, two weeks following cell injection (treatment day 1,tumor day 15) treatment was started. Cpd. No. 4 and Cpd. No. 6 weregiven intravenously, in a solution of 25% PEG 400: 9% Cremophor EL: 66%PBS, and orally in a solution of PEG 200.

Assessment

Mice were checked daily and weighed 3 times per week. When the firstsigns of illness appeared all mice were weighed daily thereafter. Signsof impending illness were weight loss, hunched and scruffy or paleappearance, decreased mobility, partial paralysis in hind limbs,distended abdomen, eye problems, respiratory problems. An animal waseuthanized when there was either >20% weight loss, full hind limbparalysis, or the presence of several symptoms in one individual. Micewere euthanized with C02 overdose. The spleen was removed, photographedwith a ruler, weighed and divided into 3 portions for 1) formalinfixation for paraffin sections 2) embedding in a mold in OCT medium forfrozen sections 3) liquid nitrogen snap freezing pieces in a microfugetube for later analysis. The sternum was removed and fixed in formalinfor bone marrow paraffin sections. See FIG. 4 and FIG. 5.

Example 10 Western Blot Analysis

RS4;11 cells were treated with Cpd. No. 4 and Cpd. No. 6 (MDM2degraders) or with Cpd. B and Cpd. C (MDM2 inhibitors) for 2 hr. MDM2and p53 proteins were probed using specific antibodies. GAPDH was usedas the loading control. Western blot analysis in shows that Cpd. No. 4and Cpd. No. 6 reduce MDM2 protein and increase p53 protein level, andthat Cpd. B and Cpd. C increase MDM2 and p53 protein levels in RS4;11cells. See FIG. 6. The structures of Cpd. B (see Compound Example No. 24of U.S. Pat. No. 8,629,141) and Cpd. C are:

22RV1 cells were treated with Cpd. No. 4 and Cpd. D (MDM2 degraders) orwith Cpd. A (MDM2 inhibitor) for 2 hr. MDM2 and p53 proteins were probedusing specific antibodies. GAPDH was used as the loading control.Western blot analysis in shows that Cpd. No. 4 and Cpd. D reduce MDM2protein and increase p53 protein level, and that Cpd. A increases MDM2and p53 protein levels in 22RV1 cells. See FIG. 7.

Example 11 Pharmacokinetics

The pharmacokinetics of Cpd. Nos. 4 and 6, and Cpd. D were evaluated inmice. The oral and IV dose amounts and relevant pharmacokineticparameters are provided in Table 6.

TABLE 6 Compound Route DOSE (mg/kg) AUC (h*ng/mL) F (%) Cpd. D IV 10193480 PO 50 12277 1.27 Cpd No. 4 IV 10 155561 PO 50 7248 0.93 Cpd No. 6IV 10 153758 PO 50 43544 5.7

In a separate PK experiment, the plasma concentrations of Cpd. D, andCpd Nos. 4, 6, and 14 were evaluated in mice following an oral dose of50 mg/kg at the time points indicated in Tables 7-10, respectively.

TABLE 7 Plasma PO 50 mg/kg Mouse 1 Mouse 2 Average Time Cpd. D (h)Concentration (ng/mL) 1 78.0 77.8 77.9 3 510 738 624 6 234 594 414

TABLE 8 Plasma PO 50 mg/kg Mouse 1 Mouse 2 Mean SD Time Cpd. No. 4 (h)Concentration (ng/mL) 1 0.231 1.01 0.62 0.55 3 902 1730 1316.00 585.48 6231 446 338.50 152.03

TABLE 9 Plasma PO 50 mg/kg Mouse 1 Mouse 2 Mean SD Time Cpd. No. 6 (h)Concentration (ng/mL) 1 0.576 0.257 0.42 0.23 3 3110 3330 3220.00 155.566 2320 2430 2375.00 77.78

TABLE 10 Plasma PO 50 mg/kg Mouse 1 Mouse 2 Average Time Cpd. No. 14 (h)Concentration (ng/mL) 1 4060 2550 3305 3 6880 8050 7465 6 7660 8810 8235

It is to be understood that the foregoing embodiments andexemplifications are not intended to be limiting in any respect to thescope of the disclosure, and that the claims presented herein areintended to encompass all embodiments and exemplifications whether ornot explicitly presented herein.

All patents and publications cited herein are fully incorporated byreference in their entirety.

What is claimed is:
 1. A compound of Formula I:

wherein: R^(1a) and R^(1b) are independently selected from the groupconsisting of hydrogen, fluoro, and chloro; R^(2a) and R^(2b) areindependently selected from the group consisting of hydrogen, fluoro,and chloro; R^(3a) and R^(3b) taken together with the carbon atom towhich they are attached form a cyclobutyl, cyclopentyl, or cyclohexylgroup that is unsubstituted or substituted with one or two methylgroups; R⁴ is selected from the group consisting of hydrogen, methyl,and ethyl; X is

wherein the bond projecting to the right is attached to —C(═O)—Y-L-Z-A;each R⁵ is independently selected from the group consisting of hydrogenand methyl; R⁶ is selected from the group consisting of hydrogen,fluoro, chloro, methyl, and methoxy; Y is —N(H)—; wherein the bondprojecting to the right is attached to -L-Z-A; L is selected from thegroup consisting of —(CH₂)_(m) and —(CH₂CH₂O)_(n)— m is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, or 10; n is 2, 3, 4, 5, or 6; Z is absent; A is

or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound of claim 1 selected from the group consisting of


3. The compound of claim 1, wherein the pharmaceutically acceptable saltis the ethane-1,2-disulfonic acid salt or the naphthalene-1,5-disulfonicacid salt.
 4. A pharmaceutical composition comprising the compound ofclaim 1, or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 5. A method of treating a subjectin need thereof comprising administering to the subject atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt or solvate thereof, wherein the subjecthas cancer.
 6. The method of claim 5, wherein the cancer is any one ormore of the cancers of Table
 2. 7. The method of claim 5, wherein thecancer is a hematological cancer.
 8. The method of claim 7, wherein thehematological cancer is any one or more of the cancers of Table
 3. 9. Akit comprising the compound of claim 1, or a pharmaceutically acceptablesalt or solvate thereof, and instructions for administering thecompound, or a pharmaceutically acceptable salt or solvate thereof, to asubject having cancer.
 10. A method of treating a subject having cancercomprising: (a) determining whether an overexpression of MDM2 is presentor absent in a biological sample taken from the subject; and (b)administering a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof, to the subject if anoverexpression of MDM2 is present in the biological sample.
 11. Amethod, comprising administering a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt or solvatethereof, to a subject in need thereof, wherein: (a) the subject hascancer; and (b) the cancer is characterized as having an overexpressionof MDM2.
 12. The method of claim 7, wherein the hematological cancer isacute lymphocytic leukemia, chronic lymphocytic leukemia, or acutemyeloid leukemia.